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Gregory, Simon Gray

Overview:

My principal area of research involves elucidating the molecular mechanisms underlying multi-factorial diseases. My lab is primarily interested identifying the complex genetic factors that give rise to multiple sclerosis, autism and cardiovascular disease. We are using targeted approaches to identify differential methylation of the oxytocin receptor gene (OXTR) in individuals with autism, and applying these data to an NICHD funded ACE award, SOARS-B, to assess long term use of oxytocin nasal spray to improve social reciprocity in 300 children with autism, and for which we are developing e/genetic and transcriptomic predictors of response and effects of long term drug exposure. My MS laboratories at Duke University and the David H Murdock Research Institute (DHMRI) are using cell signaling and immune cell flow sorting to establish the role of IL7R signaling in the development of MS; we have developed three novel mouse strains to induce EAE susceptibility and to investigate allele and splicing specific effects of IL7R in these novel MS models; I am PI of the MURDOCK-MS collection, a cross sectional MS cohort of ~1000 MS patients that will provide the basis for genetic, genomic and metabolomic biomarker identification of MS disease development and progression. I am also Director of the nascent Duke Center for Research in Autoimmunity and MS within the Duke Department of Neurology.

Positions:

Professor in Neurology

Neurology, MS & Neuroimmunology
School of Medicine

Research Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of Duke Molecular Physiology Institute

Duke Molecular Physiology Institute
School of Medicine

Education:

B.A.Sc. 1990

B.A.Sc. — RMIT University (Australia)

Ph.D. 2003

Ph.D. — Open University, Milton Keynes (U.K.)

News:

Grants:

Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
May 11, 2018
End Date
April 30, 2023

Postdoctoral Training in Genomic Medicine Research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
June 14, 2017
End Date
May 31, 2022

Copper Homeostasis in Mammals

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 01, 2004
End Date
February 28, 2022

Characterizing the (epi)genetics of oxytocin response in clinical and animal models

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 14, 2017
End Date
January 31, 2022

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Genetics Training Grant

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 1979
End Date
June 30, 2020

Epigenomics in insulin resistance associated overactive bladder

Administered By
Obstetrics and Gynecology, Urogynecology
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
June 01, 2017
End Date
May 31, 2020

Networks of nutritional stress in human pancreatic islet cells

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
Merck Sharp & Dohme
Role
Investigator
Start Date
June 18, 2018
End Date
December 17, 2019

Specific and Pervasive Symptoms in Adults with Multiple Sclerosis Using the MURDOCK-MS Dataset: A Secondary Analysis

Administered By
School of Nursing
AwardedBy
National Institutes of Health
Role
Significant Contributor
Start Date
September 01, 2017
End Date
August 31, 2019

Systems Biology Approaches for Predicting Cardiometabolic Risk in Persons Living with HIV

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 03, 2015
End Date
August 31, 2018

Identifying Genetic and Epigenetic Signatures of Treatment Response to Oxytocin in Humans and Mice

Administered By
Duke Molecular Physiology Institute
AwardedBy
Autism Speaks
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 30, 2018

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
AwardedBy
Prostate Cancer Foundation
Role
Investigator
Start Date
August 01, 2014
End Date
August 01, 2018

Development of a Prognostic Marker for Lung Cancer Using Analysis of Tumor Evolution

Administered By
Radiology, Cardiothoracic Imaging
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
August 01, 2015
End Date
July 31, 2018

SOARS-B

Administered By
Psychiatry, Child & Family Mental Health and Developmental Neuroscience
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 04, 2012
End Date
May 31, 2018

Integration of CT imaging features with cell-free plasma DNA as biomarkers for early lung cancer detection in patients with indeterminate pulmonary nodules

Administered By
Radiology, Cardiothoracic Imaging
AwardedBy
Society of Thoracic Radiology
Role
Collaborator
Start Date
January 01, 2016
End Date
January 15, 2018

SRA for Stephanie Arvai

Administered By
Duke Molecular Physiology Institute
AwardedBy
University of Texas Medical Branch
Role
Principal Investigator
Start Date
February 01, 2016
End Date
November 30, 2016

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Metabolomic Quantitative Trait Locus (mQTL) Genetic Mapping in Human CVD

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 15, 2009
End Date
May 31, 2016

A role for pathogen-induced IL-10 production in susceptibility to MS

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Multiple Sclerosis Society
Role
Co Investigator
Start Date
September 01, 2014
End Date
August 31, 2015

Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B)

Administered By
Duke Molecular Physiology Institute
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
September 04, 2012
End Date
August 01, 2015

Defining the Functional Role of a Novel MS Susceptibility Gene, IL7R alpha chain

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2009
End Date
June 30, 2015

Linkage and candidate gene analysis in non-syndromic Chiari type I

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 2009
End Date
March 31, 2015

Study of Genetic Basis of Fuchs Corneal Dystrophy

Administered By
Ophthalmology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 15, 2007
End Date
August 31, 2013

Genetic Mediators of Metabolic Cardiovascular Disease Risk

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2009
End Date
May 31, 2012

Candidate Genes and Longitudinal Disability Phenotypes

Administered By
Center for the Study of Aging and Human Development
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 15, 2006
End Date
April 30, 2012

Molecular mechanisms of altered calcium sensing in human parathyroid disease

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
June 01, 2010
End Date
January 31, 2012

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Hereditary basis of neural tube defects

Administered By
Medicine, Medical Genetics
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 1999
End Date
April 30, 2010

Genotyping - Illumina Methylation Analysis of DNA Samples

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institute of Environmental Health Sciences
Role
Principal Investigator
Start Date
September 16, 2008
End Date
February 28, 2010

Genotyping - Methlylation Infinium Chips

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institute of Environmental Health Sciences
Role
Principal Investigator
Start Date
September 16, 2008
End Date
February 28, 2010

Molecular Dissection of Cardiovascular Disease: From Genes to Models to Function

Administered By
Medicine, Medical Genetics
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 15, 2007
End Date
July 31, 2009

GENECARD: Gene identification in Early-Onset CAD

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2003
End Date
March 31, 2009

Molecular Genetics of Coronary Artery Disease

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2006
End Date
July 31, 2007

High-Resolution CGH Characterization of Brain Tumors

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 15, 2004
End Date
July 31, 2006
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Publications:

Associations Between Residential Proximity to Traffic and Vascular Disease in a Cardiac Catheterization Cohort.

Exposure to mobile source emissions is nearly ubiquitous in developed nations and is associated with multiple adverse health outcomes. There is an ongoing need to understand the specificity of traffic exposure associations with vascular outcomes, particularly in individuals with cardiovascular disease.We performed a cross-sectional study using 2124 individuals residing in North Carolina, United States, who received a cardiac catheterization at the Duke University Medical Center. Traffic-related exposure was assessed via 2 metrics: (1) the distance between the primary residence and the nearest major roadway; and (2) location of the primary residence in regions defined based on local traffic patterns. We examined 4 cardiovascular disease outcomes: hypertension, peripheral arterial disease, the number of diseased coronary vessels, and recent myocardial infarction. Statistical models were adjusted for race, sex, smoking, type 2 diabetes mellitus, body mass index, hyperlipidemia, and home value. Results are expressed in terms of the odds ratio (OR). A 23% decrease in residential distance to major roadways was associated with higher prevalence of peripheral arterial disease (OR=1.29; 95% confidence interval, 1.08-1.55) and hypertension (OR=1.15; 95% confidence interval, 1.01-1.31). Associations with peripheral arterial disease were strongest in men (OR=1.42; 95% confidence interval, 1.17-1.74) while associations with hypertension were strongest in women (OR=1.21; 95% confidence interval, 0.99-1.49). Neither myocardial infarction nor the number of diseased coronary vessels were associated with traffic exposure.Traffic-related exposure is associated with peripheral arterial disease and hypertension while no associations are observed for 2 coronary-specific vascular outcomes.

Authors
Ward-Caviness, CK; Kraus, WE; Blach, C; Haynes, CS; Dowdy, E; Miranda, ML; Devlin, R; Diaz-Sanchez, D; Cascio, WE; Mukerjee, S; Stallings, C; Smith, LA; Gregory, SG; Shah, SH; Neas, LM; Hauser, ER
MLA Citation
Ward-Caviness, CK, Kraus, WE, Blach, C, Haynes, CS, Dowdy, E, Miranda, ML, Devlin, R, Diaz-Sanchez, D, Cascio, WE, Mukerjee, S, Stallings, C, Smith, LA, Gregory, SG, Shah, SH, Neas, LM, and Hauser, ER. "Associations Between Residential Proximity to Traffic and Vascular Disease in a Cardiac Catheterization Cohort." Arteriosclerosis, thrombosis, and vascular biology 38.1 (January 2018): 275-282.
PMID
29191927
Source
epmc
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
38
Issue
1
Publish Date
2018
Start Page
275
End Page
282
DOI
10.1161/atvbaha.117.310003

Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin.

The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell-mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations.

Authors
Kanayama, M; Xu, S; Danzaki, K; Gibson, JR; Inoue, M; Gregory, SG; Shinohara, ML
MLA Citation
Kanayama, M, Xu, S, Danzaki, K, Gibson, JR, Inoue, M, Gregory, SG, and Shinohara, ML. "Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin." Nature immunology 18.9 (September 2017): 973-984.
PMID
28671690
Source
epmc
Published In
Nature Immunology
Volume
18
Issue
9
Publish Date
2017
Start Page
973
End Page
984
DOI
10.1038/ni.3791

Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome.

Although circulating microRNA (miRNAs) have emerged as biomarkers predicting mortality in acute coronary syndrome (ACS), more data are needed to understand these mechanisms. Mapping miRNAs to high-risk traits may identify miRNAs involved in pathways conferring risk for poor outcome in ACS. We aim to investigate the relationship between circulating miRNAs and high-risk traits in non-ST-segment elevation acute coronary syndrome (NSTE-ACS).Whole-genome miRNA sequencing was performed on RNA extracted from whole blood of 199 patients with NSTE-ACS. Generalized linear models were used to test associations of miRNAs and 13 high-risk clinical traits, including the Global Registry of Acute Coronary Events (GRACE) score, a widely validated risk score for mortality in NSTE-ACS.There were 205 nominally significant miRNA-risk factor associations (p < 0.05) observed. Significant associations occurred most frequently with chronic heart failure (HF) (43 miRs), GRACE risk score (30 miRs), and renal function (32 miRs). In hierarchical cluster analysis, chronic HF and GRACE risk score clustered most tightly together, sharing 14 miRNAs with matching fold-change direction. Controlling for a false discovery rate of 5%, chronic HF was significantly associated with lower circulating levels of miR-3135b (p < 0.0006), miR-126-5p (p < 0.0001), miR-142-5p (p = 0.0004) and miR-144-5p (p = 0.0007), while increasing GRACE risk score inversely correlated with levels of miR-3135b (p < 0.0001) and positively correlated with levels of miR-28-3p (p = 0.0002).Circulating miRs clustered around two powerful traits for mortality risk in NSTE-ACS. MiR-3135b, which was under-expressed in chronic HF and increasing GRACE risk score, and miR-28-3p, which has no known association with cardiovascular disease, warrant further investigation.

Authors
Wang, A; Kwee, LC; Grass, E; Neely, ML; Gregory, SG; Fox, KAA; Armstrong, PW; White, HD; Ohman, EM; Roe, MT; Shah, SH; Chan, MY
MLA Citation
Wang, A, Kwee, LC, Grass, E, Neely, ML, Gregory, SG, Fox, KAA, Armstrong, PW, White, HD, Ohman, EM, Roe, MT, Shah, SH, and Chan, MY. "Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome." Atherosclerosis 261 (June 2017): 19-25.
PMID
28437675
Source
epmc
Published In
Atherosclerosis
Volume
261
Publish Date
2017
Start Page
19
End Page
25
DOI
10.1016/j.atherosclerosis.2017.03.041

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy.

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10-8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.

Authors
Afshari, NA; Igo, RP; Morris, NJ; Stambolian, D; Sharma, S; Pulagam, VL; Dunn, S; Stamler, JF; Truitt, BJ; Rimmler, J; Kuot, A; Croasdale, CR; Qin, X; Burdon, KP; Riazuddin, SA; Mills, R; Klebe, S; Minear, MA; Zhao, J; Balajonda, E; Rosenwasser, GO; Baratz, KH; Mootha, VV; Patel, SV; Gregory, SG; Bailey-Wilson, JE; Price, MO; Price, FW; Craig, JE; Fingert, JH; Gottsch, JD; Aldave, AJ; Klintworth, GK; Lass, JH; Li, Y-J; Iyengar, SK
MLA Citation
Afshari, NA, Igo, RP, Morris, NJ, Stambolian, D, Sharma, S, Pulagam, VL, Dunn, S, Stamler, JF, Truitt, BJ, Rimmler, J, Kuot, A, Croasdale, CR, Qin, X, Burdon, KP, Riazuddin, SA, Mills, R, Klebe, S, Minear, MA, Zhao, J, Balajonda, E, Rosenwasser, GO, Baratz, KH, Mootha, VV, Patel, SV, Gregory, SG, Bailey-Wilson, JE, Price, MO, Price, FW, Craig, JE, Fingert, JH, Gottsch, JD, Aldave, AJ, Klintworth, GK, Lass, JH, Li, Y-J, and Iyengar, SK. "Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy." Nature communications 8 (March 30, 2017): 14898-.
PMID
28358029
Source
epmc
Published In
Nature Communications
Volume
8
Publish Date
2017
Start Page
14898
DOI
10.1038/ncomms14898

Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer.

Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach.Experimental Design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential aCGH analyses of CTCs in the context of enzalutamide therapy.Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2 Analysis of aCGH in a sample with sequential enzalutamide-resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone.Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development. Clin Cancer Res; 23(5); 1346-57. ©2016 AACR.

Authors
Gupta, S; Li, J; Kemeny, G; Bitting, RL; Beaver, J; Somarelli, JA; Ware, KE; Gregory, S; Armstrong, AJ
MLA Citation
Gupta, S, Li, J, Kemeny, G, Bitting, RL, Beaver, J, Somarelli, JA, Ware, KE, Gregory, S, and Armstrong, AJ. "Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 23.5 (March 2017): 1346-1357.
PMID
27601596
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
5
Publish Date
2017
Start Page
1346
End Page
1357
DOI
10.1158/1078-0432.ccr-16-1211

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

Authors
Galarza-Muñoz, G; Briggs, FBS; Evsyukova, I; Schott-Lerner, G; Kennedy, EM; Nyanhete, T; Wang, L; Bergamaschi, L; Widen, SG; Tomaras, GD; Ko, DC; Bradrick, SS; Barcellos, LF; Gregory, SG; Garcia-Blanco, MA
MLA Citation
Galarza-Muñoz, G, Briggs, FBS, Evsyukova, I, Schott-Lerner, G, Kennedy, EM, Nyanhete, T, Wang, L, Bergamaschi, L, Widen, SG, Tomaras, GD, Ko, DC, Bradrick, SS, Barcellos, LF, Gregory, SG, and Garcia-Blanco, MA. "Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk." Cell 169.1 (March 2017): 72-84.e13.
PMID
28340352
Source
epmc
Published In
Cell
Volume
169
Issue
1
Publish Date
2017
Start Page
72
End Page
84.e13
DOI
10.1016/j.cell.2017.03.007

A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic.

Air pollution is a worldwide contributor to cardiovascular disease mortality and morbidity. Traffic-related air pollution is a widespread environmental exposure and is associated with multiple cardiovascular outcomes such as coronary atherosclerosis, peripheral arterial disease, and myocardial infarction. Despite the recognition of the importance of both genetic and environmental exposures to the pathogenesis of cardiovascular disease, studies of how these two contributors operate jointly are rare. We performed a genome-wide interaction study (GWIS) to examine gene-traffic exposure interactions associated with coronary atherosclerosis. Using race-stratified cohorts of 538 African-Americans (AA) and 1562 European-Americans (EA) from a cardiac catheterization cohort (CATHGEN), we identify gene-by-traffic exposure interactions associated with the number of significantly diseased coronary vessels as a measure of chronic atherosclerosis. We found five suggestive (P<1x10-5) interactions in the AA GWIS, of which two (rs1856746 and rs2791713) replicated in the EA cohort (P < 0.05). Both SNPs are in the PIGR-FCAMR locus and are eQTLs in lymphocytes. The protein products of both PIGR and FCAMR are implicated in inflammatory processes. In the EA GWIS, there were three suggestive interactions; none of these replicated in the AA GWIS. All three were intergenic; the most significant interaction was in a regulatory region associated with SAMSN1, a gene previously associated with atherosclerosis and B cell activation. In conclusion, we have uncovered several novel genes associated with coronary atherosclerosis in individuals chronically exposed to increased ambient concentrations of traffic air pollution. These genes point towards inflammatory pathways that may modify the effects of air pollution on cardiovascular disease risk.

Authors
Ward-Caviness, CK; Neas, LM; Blach, C; Haynes, CS; LaRocque-Abramson, K; Grass, E; Dowdy, ZE; Devlin, RB; Diaz-Sanchez, D; Cascio, WE; Miranda, ML; Gregory, SG; Shah, SH; Kraus, WE; Hauser, ER
MLA Citation
Ward-Caviness, CK, Neas, LM, Blach, C, Haynes, CS, LaRocque-Abramson, K, Grass, E, Dowdy, ZE, Devlin, RB, Diaz-Sanchez, D, Cascio, WE, Miranda, ML, Gregory, SG, Shah, SH, Kraus, WE, and Hauser, ER. "A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic." PloS one 12.3 (January 2017): e0173880-.
PMID
28355232
Source
epmc
Published In
PloS one
Volume
12
Issue
3
Publish Date
2017
Start Page
e0173880
DOI
10.1371/journal.pone.0173880

Human centromere repositioning within euchromatin after partial chromosome deletion.

Centromeres are defined by a specialized chromatin organization that includes nucleosomes that contain the centromeric histone variant centromere protein A (CENP-A) instead of canonical histone H3. Studies in various organisms have shown that centromeric chromatin (i.e., CENP-A chromatin or centrochromatin) exhibits plasticity, in that it can assemble on different types of DNA sequences. However, once established on a chromosome, the centromere is maintained at the same position. In humans, this location is the highly homogeneous repetitive DNA alpha satellite. Mislocalization of centromeric chromatin to atypical locations can lead to genome instability, indicating that restriction of centromeres to a distinct genomic position is important for cell and organism viability. Here, we describe a rearrangement of Homo sapiens chromosome 17 (HSA17) that has placed alpha satellite DNA next to euchromatin. We show that on this mutant chromosome, CENP-A chromatin has spread from the alpha satellite into the short arm of HSA17, establishing a ∼700 kb hybrid centromeric domain that spans both repetitive and unique sequences and changes the expression of at least one gene over which it spreads. Our results illustrate the plasticity of human centromeric chromatin and suggest that heterochromatin normally constrains CENP-A chromatin onto alpha satellite DNA. This work highlights that chromosome rearrangements, particularly those that remove the pericentromere, create opportunities for centromeric nucleosomes to move into non-traditional genomic locations, potentially changing the surrounding chromatin environment and altering gene expression.

Authors
Sullivan, LL; Maloney, KA; Towers, AJ; Gregory, SG; Sullivan, BA
MLA Citation
Sullivan, LL, Maloney, KA, Towers, AJ, Gregory, SG, and Sullivan, BA. "Human centromere repositioning within euchromatin after partial chromosome deletion." Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 24.4 (December 2016): 451-466.
PMID
27581771
Source
epmc
Published In
Chromosome Research
Volume
24
Issue
4
Publish Date
2016
Start Page
451
End Page
466
DOI
10.1007/s10577-016-9536-6

An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.

Inflammation induced by innate immunity influences the development of T cell-mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome-independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4+ T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.

Authors
Inoue, M; Chen, P-H; Siecinski, S; Li, Q-J; Liu, C; Steinman, L; Gregory, SG; Benner, E; Shinohara, ML
MLA Citation
Inoue, M, Chen, P-H, Siecinski, S, Li, Q-J, Liu, C, Steinman, L, Gregory, SG, Benner, E, and Shinohara, ML. "An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage." Nature neuroscience 19.12 (December 2016): 1599-1609.
PMID
27820602
Source
epmc
Published In
Nature Neuroscience
Volume
19
Issue
12
Publish Date
2016
Start Page
1599
End Page
1609
DOI
10.1038/nn.4421

Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.

On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are significantly associated with lower risk of mortality at advanced ages. Such a significant association is replicated in two independent Han Chinese CLHLS cohorts (p = 0.028-0.048 in the discovery and replication cohorts, and p = 0.003-0.016 in the combined dataset). We found the associations between tea drinking and reduced mortality are much stronger among carriers of the FOXO1A-209 genotype compared to non-carriers, and drinking tea is associated with a reversal of the negative effects of carrying FOXO1A-209 minor alleles, that is, from a substantially increased mortality risk to substantially reduced mortality risk at advanced ages. The impacts are considerably stronger among those who carry two copies of the FOXO1A minor allele than those who carry one copy. On the basis of previously reported experiments on human cell models concerning FOXO1A-by-tea-compounds interactions, we speculate that results in the present study indicate that tea drinking may inhibit FOXO1A-209 gene expression and its biological functions, which reduces the negative impacts of FOXO1A-209 gene on longevity (as reported in the literature) and offers protection against mortality risk at oldest-old ages. Our empirical findings imply that the health outcomes of particular nutritional interventions, including tea drinking, may, in part, depend upon individual genetic profiles, and the research on the effects of nutrigenomics interactions could potentially be useful for rejuvenation therapies in the clinic or associated healthy aging intervention programs.

Authors
Zeng, Y; Chen, H; Ni, T; Ruan, R; Nie, C; Liu, X; Feng, L; Zhang, F; Lu, J; Li, J; Li, Y; Tao, W; Gregory, SG; Gottschalk, W; Lutz, MW; Land, KC; Yashin, A; Tan, Q; Yang, Z; Bolund, L; Ming, Q; Yang, H; Min, J; Willcox, DC; Willcox, BJ; Gu, J; Hauser, E; Tian, X-L; Vaupel, JW
MLA Citation
Zeng, Y, Chen, H, Ni, T, Ruan, R, Nie, C, Liu, X, Feng, L, Zhang, F, Lu, J, Li, J, Li, Y, Tao, W, Gregory, SG, Gottschalk, W, Lutz, MW, Land, KC, Yashin, A, Tan, Q, Yang, Z, Bolund, L, Ming, Q, Yang, H, Min, J, Willcox, DC, Willcox, BJ, Gu, J, Hauser, E, Tian, X-L, and Vaupel, JW. "Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages." Rejuvenation research 19.3 (June 2016): 195-203.
Website
http://hdl.handle.net/10161/14659
PMID
26414954
Source
epmc
Published In
Rejuvenation Research
Volume
19
Issue
3
Publish Date
2016
Start Page
195
End Page
203
DOI
10.1089/rej.2015.1737

Novel loci and pathways significantly associated with longevity.

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

Authors
Zeng, Y; Nie, C; Min, J; Liu, X; Li, M; Chen, H; Xu, H; Wang, M; Ni, T; Li, Y; Yan, H; Zhang, J-P; Song, C; Chi, L-Q; Wang, H-M; Dong, J; Zheng, G-Y; Lin, L; Qian, F; Qi, Y; Liu, X; Cao, H; Wang, Y; Zhang, L; Li, Z; Zhou, Y; Wang, Y; Lu, J; Li, J; Qi, M; Bolund, L; Yashin, A; Land, KC; Gregory, S; Yang, Z; Gottschalk, W; Tao, W; Wang, J; Wang, J; Xu, X; Bae, H; Nygaard, M; Christiansen, L; Christensen, K; Franceschi, C; Lutz, MW; Gu, J; Tan, Q; Perls, T; Sebastiani, P; Deelen, J; Slagboom, E et al.
MLA Citation
Zeng, Y, Nie, C, Min, J, Liu, X, Li, M, Chen, H, Xu, H, Wang, M, Ni, T, Li, Y, Yan, H, Zhang, J-P, Song, C, Chi, L-Q, Wang, H-M, Dong, J, Zheng, G-Y, Lin, L, Qian, F, Qi, Y, Liu, X, Cao, H, Wang, Y, Zhang, L, Li, Z, Zhou, Y, Wang, Y, Lu, J, Li, J, Qi, M, Bolund, L, Yashin, A, Land, KC, Gregory, S, Yang, Z, Gottschalk, W, Tao, W, Wang, J, Wang, J, Xu, X, Bae, H, Nygaard, M, Christiansen, L, Christensen, K, Franceschi, C, Lutz, MW, Gu, J, Tan, Q, Perls, T, Sebastiani, P, Deelen, J, and Slagboom, E et al. "Novel loci and pathways significantly associated with longevity." Scientific reports 6 (February 25, 2016): 21243-.
Website
http://hdl.handle.net/10161/14652
PMID
26912274
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
21243
DOI
10.1038/srep21243

Integrated metabolomic and transcriptomic profiles of males with multiple sclerosis

Authors
Cote, SA; Gregory, SG; Winnike, J; Knagge, K; Ilkayeva, O; O'Connell, T; Bain, J; Muehlbauer, M; Maichle, S; Newby, LK; Zhang, X
MLA Citation
Cote, SA, Gregory, SG, Winnike, J, Knagge, K, Ilkayeva, O, O'Connell, T, Bain, J, Muehlbauer, M, Maichle, S, Newby, LK, and Zhang, X. "Integrated metabolomic and transcriptomic profiles of males with multiple sclerosis." February 2016.
Source
wos-lite
Published In
Multiple Sclerosis
Volume
22
Publish Date
2016
Start Page
9
End Page
10

Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.

There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic ("traffic exposure")-a recognized vascular disease risk factor-on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10-8) in European-Americans. Rs755249 is located in the 3' untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10-6) and rs1180341 (tibial artery, eQTL P = 5.3x10-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes.

Authors
Ward-Caviness, CK; Neas, LM; Blach, C; Haynes, CS; LaRocque-Abramson, K; Grass, E; Dowdy, E; Devlin, RB; Diaz-Sanchez, D; Cascio, WE; Lynn Miranda, M; Gregory, SG; Shah, SH; Kraus, WE; Hauser, ER
MLA Citation
Ward-Caviness, CK, Neas, LM, Blach, C, Haynes, CS, LaRocque-Abramson, K, Grass, E, Dowdy, E, Devlin, RB, Diaz-Sanchez, D, Cascio, WE, Lynn Miranda, M, Gregory, SG, Shah, SH, Kraus, WE, and Hauser, ER. "Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease." PloS one 11.4 (January 2016): e0152670-.
PMID
27082954
Source
epmc
Published In
PloS one
Volume
11
Issue
4
Publish Date
2016
Start Page
e0152670
DOI
10.1371/journal.pone.0152670

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship.

Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs-rs1462845 and rs6788787-using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01-1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69-0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08-1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05-1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype ('A/A') fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.

Authors
Dungan, JR; Qin, X; Horne, BD; Carlquist, JF; Singh, A; Hurdle, M; Grass, E; Haynes, C; Gregory, SG; Shah, SH; Hauser, ER; Kraus, WE
MLA Citation
Dungan, JR, Qin, X, Horne, BD, Carlquist, JF, Singh, A, Hurdle, M, Grass, E, Haynes, C, Gregory, SG, Shah, SH, Hauser, ER, and Kraus, WE. "Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship." PloS one 11.5 (January 2016): e0154856-.
PMID
27187494
Source
epmc
Published In
PloS one
Volume
11
Issue
5
Publish Date
2016
Start Page
e0154856
DOI
10.1371/journal.pone.0154856

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

Authors
Kraus, WE; Muoio, DM; Stevens, R; Craig, D; Bain, JR; Grass, E; Haynes, C; Kwee, L; Qin, X; Slentz, DH; Krupp, D; Muehlbauer, M; Hauser, ER; Gregory, SG; Newgard, CB; Shah, SH
MLA Citation
Kraus, WE, Muoio, DM, Stevens, R, Craig, D, Bain, JR, Grass, E, Haynes, C, Kwee, L, Qin, X, Slentz, DH, Krupp, D, Muehlbauer, M, Hauser, ER, Gregory, SG, Newgard, CB, and Shah, SH. "Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis." PLoS genetics 11.11 (November 5, 2015): e1005553-.
Website
http://hdl.handle.net/10161/10957
PMID
26540294
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
11
Publish Date
2015
Start Page
e1005553
DOI
10.1371/journal.pgen.1005553

Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala.

Fumonisin (FB) occurs in maize and is an inhibitor of ceramide synthase (CerS). We determined the urinary FB1 (UFB1 ) and sphingoid base 1-phosphate levels in blood from women consuming maize in high and low FB exposure communities in Guatemala.FB1 intake was estimated using the UFB1 . Sphinganine 1-phosphate (Sa 1-P), sphingosine 1-phosphate (So 1-P), and the Sa 1-P/So 1-P ratio were determined in blood spots collected on absorbent paper at the same time as urine collection. In the first study, blood spots and urine were collected every 3 months (March 2011 to February 2012) from women living in low (Chimaltenango and Escuintla) and high (Jutiapa) FB exposure communities (1240 total recruits). The UFB1 , Sa 1-P/So 1-P ratio, and Sa 1-P/mL in blood spots were significantly higher in the high FB1 intake community compared to the low FB1 intake communities. The results were confirmed in a follow-up study (February 2013) involving 299 women living in low (Sacatepéquez) and high (Santa Rosa and Chiquimula) FB exposure communities.High levels of FB1 intake are correlated with changes in Sa 1-P and the Sa 1-P/So 1-P ratio in human blood in a manner consistent with FB1 inhibition of CerS.

Authors
Riley, RT; Torres, O; Matute, J; Gregory, SG; Ashley-Koch, AE; Showker, JL; Mitchell, T; Voss, KA; Maddox, JR; Gelineau-van Waes, JB
MLA Citation
Riley, RT, Torres, O, Matute, J, Gregory, SG, Ashley-Koch, AE, Showker, JL, Mitchell, T, Voss, KA, Maddox, JR, and Gelineau-van Waes, JB. "Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala." Molecular nutrition & food research 59.11 (November 2015): 2209-2224.
PMID
26264677
Source
epmc
Published In
Molecular Nutrition & Food Research
Volume
59
Issue
11
Publish Date
2015
Start Page
2209
End Page
2224
DOI
10.1002/mnfr.201500499

Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients.

The relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollution on human health.We examined associations between roadway proximity and traffic exposure zones, as markers of TRAP exposure, and metabolic biomarkers for cardiovascular disease risk in a cohort of patients undergoing cardiac catheterization.We performed a cross-sectional study of 2,124 individuals residing in North Carolina (USA). Roadway proximity was assessed via distance to primary and secondary roadways, and we used residence in traffic exposure zones (TEZs) as a proxy for TRAP. Two categories of metabolic outcomes were studied: measures associated with glucose control, and measures associated with lipid metabolism. Statistical models were adjusted for race, sex, smoking, body mass index, and socioeconomic status (SES).An interquartile-range (990 m) decrease in distance to roadways was associated with higher fasting plasma glucose (β = 2.17 mg/dL; 95% CI: -0.24, 4.59), and the association appeared to be limited to women (β = 5.16 mg/dL; 95% CI: 1.48, 8.84 compared with β = 0.14 mg/dL; 95% CI: -3.04, 3.33 in men). Residence in TEZ 5 (high-speed traffic) and TEZ 6 (stop-and-go traffic), the two traffic zones assumed to have the highest levels of TRAP, was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 8.36; 95% CI: -0.15, 16.9 and β = 5.98; 95% CI: -3.96, 15.9, for TEZ 5 and 6, respectively).Proxy measures of TRAP exposure were associated with intermediate metabolic traits associated with cardiovascular disease, including fasting plasma glucose and possibly HDL-C.

Authors
Ward-Caviness, CK; Kraus, WE; Blach, C; Haynes, CS; Dowdy, E; Miranda, ML; Devlin, RB; Diaz-Sanchez, D; Cascio, WE; Mukerjee, S; Stallings, C; Smith, LA; Gregory, SG; Shah, SH; Hauser, ER; Neas, LM
MLA Citation
Ward-Caviness, CK, Kraus, WE, Blach, C, Haynes, CS, Dowdy, E, Miranda, ML, Devlin, RB, Diaz-Sanchez, D, Cascio, WE, Mukerjee, S, Stallings, C, Smith, LA, Gregory, SG, Shah, SH, Hauser, ER, and Neas, LM. "Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients." Environmental health perspectives 123.10 (October 2015): 1007-1014.
PMID
25807578
Source
epmc
Published In
Environmental health perspectives
Volume
123
Issue
10
Publish Date
2015
Start Page
1007
End Page
1014
DOI
10.1289/ehp.1306980

Epigenetic profiling identifies novel genes for ascending aortic aneurysm formation with bicuspid aortic valves.

  Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized.  We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.  Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves.  Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays.  Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test.    Twenty-seven probes in 9 genes showed significant differential methylation and expression (P<5.5x10-4).  The top gene was protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10-5) in bicuspid patients, as compared to tricuspid patients.  Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range:  -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissections  Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms.  The top gene was PTPN22, which is involved in T-cell receptor signaling and associated with various immune disorders.  These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

Authors
Shah, AA; Gregory, SG; Krupp, D; Feng, S; Dorogi, A; Haynes, C; Grass, E; Lin, SS; Hauser, ER; Kraus, WE; Shah, SH; Hughes, GC
MLA Citation
Shah, AA, Gregory, SG, Krupp, D, Feng, S, Dorogi, A, Haynes, C, Grass, E, Lin, SS, Hauser, ER, Kraus, WE, Shah, SH, and Hughes, GC. "Epigenetic profiling identifies novel genes for ascending aortic aneurysm formation with bicuspid aortic valves." The heart surgery forum 18.4 (August 30, 2015): E134-E139.
PMID
26334848
Source
epmc
Published In
The heart surgery forum
Volume
18
Issue
4
Publish Date
2015
Start Page
E134
End Page
E139
DOI
10.1532/hsf.1247

Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome.

The aim of the article is to examine the psychological impact, specifically symptoms of grief, post-traumatic stress and depression, in women and men who either terminated or continued a pregnancy following prenatal diagnosis of a lethal fetal defect.This project investigated a diagnostically homogeneous group composed of 158 women and 109 men who lost a pregnancy to anencephaly, a lethal neural tube defect. Participants completed the Perinatal Grief Scale, Impact of Event Scale - Revised and Beck Depression Inventory-II, which measure symptoms of grief, post-traumatic stress and depression, respectively. Demographics, religiosity and pregnancy choices were also collected. Gender-specific analysis of variance was performed for instrument total scores and subscales.Women who terminated reported significantly more despair (p = 0.02), avoidance (p = 0.008) and depression (p = 0.04) than women who continued the pregnancy. Organizational religious activity was associated with a reduction in grief (Perinatal Grief Scale subscales) in both women (p = 0.02, p = 0.04 and p = 0.03) and men (p = 0.047).There appears to be a psychological benefit to women to continue the pregnancy following a lethal fetal diagnosis. Following a lethal fetal diagnosis, the risks and benefits, including psychological effects, of termination and continuation of pregnancy should be discussed in detail with an effort to be as nondirective as possible.

Authors
Cope, H; Garrett, ME; Gregory, S; Ashley-Koch, A
MLA Citation
Cope, H, Garrett, ME, Gregory, S, and Ashley-Koch, A. "Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome." Prenatal diagnosis 35.8 (August 2015): 761-768.
PMID
25872901
Source
epmc
Published In
Prenatal Diagnosis
Volume
35
Issue
8
Publish Date
2015
Start Page
761
End Page
768
DOI
10.1002/pd.4603

Comparison of GC-MS and GC×GC-MS in the analysis of human serum samples for biomarker discovery.

We compared the performance of gas chromatography time-of-flight mass spectrometry (GC-MS) and comprehensive two-dimensional gas chromatography mass spectrometry (GC×GC-MS) for metabolite biomarker discovery. Metabolite extracts from 109 human serum samples were analyzed on both platforms with a pooled serum sample analyzed after every 9 biological samples for the purpose of quality control (QC). The experimental data derived from the pooled QC samples showed that the GC×GC-MS platform detected about three times as many peaks as the GC-MS platform at a signal-to-noise ratio SNR ≥ 50, and three times the number of metabolites were identified by mass spectrum matching with a spectral similarity score Rsim ≥ 600. Twenty-three metabolites had statistically significant abundance changes between the patient samples and the control samples in the GC-MS data set while 34 metabolites in the GC×GC-MS data set showed statistically significant differences. Among these two groups of metabolite biomarkers, nine metabolites were detected in both the GC-MS and GC×GC-MS data sets with the same direction and similar magnitude of abundance changes between the control and patient sample groups. Manual verification indicated that the difference in the number of the biomarkers discovered using these two platforms was mainly due to the limited resolution of chromatographic peaks by the GC-MS platform, which can result in severe peak overlap making subsequent spectrum deconvolution for metabolite identification and quantification difficult.

Authors
Winnike, JH; Wei, X; Knagge, KJ; Colman, SD; Gregory, SG; Zhang, X
MLA Citation
Winnike, JH, Wei, X, Knagge, KJ, Colman, SD, Gregory, SG, and Zhang, X. "Comparison of GC-MS and GC×GC-MS in the analysis of human serum samples for biomarker discovery." Journal of proteome research 14.4 (April 2015): 1810-1817.
PMID
25735966
Source
epmc
Published In
Journal of Proteome Research
Volume
14
Issue
4
Publish Date
2015
Start Page
1810
End Page
1817
DOI
10.1021/pr5011923

TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone.

The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts. Tmem231 and B9d1 are essential for each other and other complex components such as Mks1 to localize to the transition zone. As in mouse, the Caenorhabditis elegans orthologue of Tmem231 localizes to and controls transition zone formation and function, suggesting an evolutionarily conserved role for Tmem231. We identified TMEM231 mutations in orofaciodigital syndrome type 3 (OFD3) and MKS patients that compromise transition zone function. Thus, Tmem231 is critical for organizing the MKS complex and controlling ciliary composition, defects in which cause OFD3 and MKS.

Authors
Roberson, EC; Dowdle, WE; Ozanturk, A; Garcia-Gonzalo, FR; Li, C; Halbritter, J; Elkhartoufi, N; Porath, JD; Cope, H; Ashley-Koch, A; Gregory, S; Thomas, S; Sayer, JA; Saunier, S; Otto, EA; Katsanis, N; Davis, EE; Attié-Bitach, T; Hildebrandt, F; Leroux, MR; Reiter, JF
MLA Citation
Roberson, EC, Dowdle, WE, Ozanturk, A, Garcia-Gonzalo, FR, Li, C, Halbritter, J, Elkhartoufi, N, Porath, JD, Cope, H, Ashley-Koch, A, Gregory, S, Thomas, S, Sayer, JA, Saunier, S, Otto, EA, Katsanis, N, Davis, EE, Attié-Bitach, T, Hildebrandt, F, Leroux, MR, and Reiter, JF. "TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone." The Journal of cell biology 209.1 (April 2015): 129-142.
PMID
25869670
Source
epmc
Published In
The Journal of Cell Biology
Volume
209
Issue
1
Publish Date
2015
Start Page
129
End Page
142
DOI
10.1083/jcb.201411087

Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation.

Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized.We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI.Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.

Authors
Lock, EF; Soldano, KL; Garrett, ME; Cope, H; Markunas, CA; Fuchs, H; Grant, G; Dunson, DB; Gregory, SG; Ashley-Koch, AE
MLA Citation
Lock, EF, Soldano, KL, Garrett, ME, Cope, H, Markunas, CA, Fuchs, H, Grant, G, Dunson, DB, Gregory, SG, and Ashley-Koch, AE. "Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation." BMC genomics 16 (January 22, 2015): 11-.
Website
http://hdl.handle.net/10161/15599
PMID
25609184
Source
epmc
Published In
BMC Genomics
Volume
16
Publish Date
2015
Start Page
11
DOI
10.1186/s12864-014-1211-8

Genetic variants associated with vein graft stenosis after coronary artery bypass grafting

© 2015 Forum Multimedia Publishing, LLC. Background: Vein graft stenosis after coronary artery bypass grafting (CABG) is common. Identifying genes associated with vein graft stenosis after CABG could reveal novel mechanisms of disease and discriminate patients at risk for graft failure. We hypothesized that genome-wide association would identify these genes. Methods: We performed a genome-wide association study on a subset of patients presenting for cardiac catheterization for concern of ischemic heart disease, who also underwent CABG and subsequent coronary angiography after CABG for clinical indications (n = 521). Cases were defined as individuals with ≥50% stenosis in any vein graft on any cardiac catheterization, and controls were defined as those who did not have vein graft stenosis on any subsequent cardiac catheterization. Multivariable logistic regression was used to assess the association between single nucleotide polymorphisms (SNPs) and vein graft stenosis. Results: Sixty-nine percent of patients had vein graft failure after CABG. Seven SNPs were significantly associated with vein graft stenosis, including intronic SNPs in the genes PALLD (Rs6854137, P = 3.77 × 10 -6 ), ARID1B (Rs184074, P = 5.97 × 10 -6 ), and TMEM123 (Rs11225247, P = 8.25 × 10 -6 ); and intergenic SNPs near the genes ABCA13 (Rs10232860, P = 4.54 × 10 -6 ), RMI2 (Rs9921338, P = 6.15 × 10 -6 ), PRM2 (Rs7198849, P = 7.27 × 10 -6 ), and TNFSF4 (Rs17346536, P = 9.33 × 10-6). Conclusions: We have identified novel genetic variants that may predispose to risk of vein graft failure after CABG, many within biologically plausible pathways. These polymorphisms merit further investigation, as they could assist in stratifying patients with multi-vessel coronary artery disease, which could lead to alterations in management and revascularization strategy.

Authors
Shah, AA; Haynes, C; Craig, DM; Sebek, J; Grass, E; Abramson, K; Hauser, ER; Gregory, SG; Kraus, WE; Smith, PK; Shah, SH
MLA Citation
Shah, AA, Haynes, C, Craig, DM, Sebek, J, Grass, E, Abramson, K, Hauser, ER, Gregory, SG, Kraus, WE, Smith, PK, and Shah, SH. "Genetic variants associated with vein graft stenosis after coronary artery bypass grafting." Heart Surgery Forum 18.1 (January 1, 2015): E1-E5.
Source
scopus
Published In
The heart surgery forum
Volume
18
Issue
1
Publish Date
2015
Start Page
E1
End Page
E5
DOI
10.1532/HSF98.2015489

Human health implications from co-exposure to aflatoxins and fumonisins in maize-based foods in Latin America: Guatemala as a case study

Authors
Torres, O; Matute, J; Gelineau-van Waes, J; Maddox, J; Gregory, S; Ashley-Koch, A; Showker, J; Voss, K; Riley, R
MLA Citation
Torres, O, Matute, J, Gelineau-van Waes, J, Maddox, J, Gregory, S, Ashley-Koch, A, Showker, J, Voss, K, and Riley, R. "Human health implications from co-exposure to aflatoxins and fumonisins in maize-based foods in Latin America: Guatemala as a case study." World Mycotoxin Journal 8.2 (January 2015): 143-159.
Source
crossref
Published In
World Mycotoxin Journal
Volume
8
Issue
2
Publish Date
2015
Start Page
143
End Page
159
DOI
10.3920/WMJ2014.1736

A blood spot method for detecting fumonisin-induced changes in putative sphingolipid biomarkers in LM/Bc mice and humans.

Fumonisins (FB) are mycotoxins found in maize. They are hypothesised risk factors for neural tube defects (NTDs) in humans living where maize is a dietary staple. In LM/Bc mice, FB1-treatment of pregnant dams induces NTDs and results in increased levels of sphingoid base 1-phosphates in blood and tissues. The increased level of sphingoid base 1-phosphates in blood is a putative biomarker for FB1 inhibition of ceramide synthase in humans. Collection of blood spots on paper from finger sticks is a relatively non-invasive way to obtain blood for biomarker analysis. The objective of this study was to develop and validate in an animal model, and ultimately in humans, a method to estimate the volume of blood collected as blood spots on absorbent paper so as to allow quantification of the molar concentration of sphingoid base 1-phosphates in blood. To accomplish this objective, blood was collected from unexposed male LM/Bc and FB1-exposed pregnant LM/Bc mice and humans and applied to two types of absorbent paper. The sphingoid base 1-phosphates, absorbance at 270 nm (A270), and total protein content (Bradford) were determined in the acetonitrile:water 5% formic acid extracts from the dried blood spots. The results show that in both mouse and human the A270, total protein, and blood volume were closely correlated and the volume of blood spotted was accurately estimated using only the A270 of the extracts. In mouse blood spots, as in tissues and embryos, the FB1-induced changes in sphingolipids were correlated with urinary FB1. The half-life of FB1 in the urine was short (<24 h) and the elevation in sphingoid base 1-phosphates in blood was also short, although more persistent than the urinary FB1.

Authors
Riley, RT; Showker, JL; Lee, CM; Zipperer, CE; Mitchell, TR; Voss, KA; Zitomer, NC; Torres, O; Matute, J; Gregory, SG; Ashley-Koch, AE; Maddox, JR; Gardner, N; Gelineau-Van Waes, JB
MLA Citation
Riley, RT, Showker, JL, Lee, CM, Zipperer, CE, Mitchell, TR, Voss, KA, Zitomer, NC, Torres, O, Matute, J, Gregory, SG, Ashley-Koch, AE, Maddox, JR, Gardner, N, and Gelineau-Van Waes, JB. "A blood spot method for detecting fumonisin-induced changes in putative sphingolipid biomarkers in LM/Bc mice and humans." Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment 32.6 (January 2015): 934-949.
PMID
25833119
Source
epmc
Published In
Food Additives & Contaminants: Part A - Chemistry, Analysis, Control, Exposure & Risk Assessment
Volume
32
Issue
6
Publish Date
2015
Start Page
934
End Page
949
DOI
10.1080/19440049.2015.1027746

Using circulating tumor cells to inform on prostate cancer biology and clinical utility.

Substantial advances in the molecular biology of prostate cancer have led to the approval of multiple new systemic agents to treat men with metastatic castration-resistant prostate cancer (mCRPC). These treatments encompass androgen receptor directed therapies, immunotherapies, bone targeting radiopharmaceuticals and cytotoxic chemotherapies. There is, however, great heterogeneity in the degree of patient benefit with these agents, thus fueling the need to develop predictive biomarkers that are able to rationally guide therapy. Circulating tumor cells (CTCs) have the potential to provide an assessment of tumor-specific biomarkers through a non-invasive, repeatable "liquid biopsy" of a patient's cancer at a given point in time. CTCs have been extensively studied in men with mCRPC, where CTC enumeration using the Cellsearch® method has been validated and FDA approved to be used in conjunction with other clinical parameters as a prognostic biomarker in metastatic prostate cancer. In addition to enumeration, more sophisticated molecular profiling of CTCs is now feasible and may provide more clinical utility as it may reflect tumor evolution within an individual particularly under the pressure of systemic therapies. Here, we review technologies used to detect and characterize CTCs, and the potential biological and clinical utility of CTC molecular profiling in men with metastatic prostate cancer.

Authors
Li, J; Gregory, SG; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Li, J, Gregory, SG, Garcia-Blanco, MA, and Armstrong, AJ. "Using circulating tumor cells to inform on prostate cancer biology and clinical utility." Critical reviews in clinical laboratory sciences 52.4 (January 2015): 191-210. (Review)
PMID
26079252
Source
epmc
Published In
Critical Reviews in Clinical Laboratory Sciences (Informa)
Volume
52
Issue
4
Publish Date
2015
Start Page
191
End Page
210
DOI
10.3109/10408363.2015.1023430

Missing genetic risk in neural tube defects: can exome sequencing yield an insight?

Neural tube defects (NTD) have a strong genetic component, with up to 70% of variance in human prevalence determined by heritable factors. Although the identification of causal DNA variants by sequencing candidate genes from functionally relevant pathways and model organisms has provided some success, alternative approaches are demanded.Next generation sequencing platforms are facilitating the production of massive amounts of sequencing data, primarily from the protein coding regions of the genome, at a faster rate and cheaper cost than has previously been possible. These platforms are permitting the identification of variants (de novo, rare, and common) that are drivers of NYTD etiology, and the cost of the approach allows for the screening of increased numbers of affected and unaffected individuals from NTD families and in simplex cases.The next generation sequencing platforms represent a powerful tool in the armory of the genetics researcher to identify the causal genetic basis of NTDs.

Authors
Krupp, DR; Soldano, KL; Garrett, ME; Cope, H; Ashley-Koch, AE; Gregory, SG
MLA Citation
Krupp, DR, Soldano, KL, Garrett, ME, Cope, H, Ashley-Koch, AE, and Gregory, SG. "Missing genetic risk in neural tube defects: can exome sequencing yield an insight?." Birth defects research. Part A, Clinical and molecular teratology 100.8 (August 2014): 642-646.
PMID
25044326
Source
epmc
Published In
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume
100
Issue
8
Publish Date
2014
Start Page
642
End Page
646
DOI
10.1002/bdra.23276

Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.

Authors
Markunas, CA; Lock, E; Soldano, K; Cope, H; Ding, C-KC; Enterline, DS; Grant, G; Fuchs, H; Ashley-Koch, AE; Gregory, SG
MLA Citation
Markunas, CA, Lock, E, Soldano, K, Cope, H, Ding, C-KC, Enterline, DS, Grant, G, Fuchs, H, Ashley-Koch, AE, and Gregory, SG. "Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics." BMC medical genomics 7 (June 25, 2014): 39-.
PMID
24962150
Source
epmc
Published In
BMC Medical Genomics
Volume
7
Publish Date
2014
Start Page
39
DOI
10.1186/1755-8794-7-39

Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.

We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD).Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included controlling for additional effects of either the TCF4 SNP rs613872 or cigarette smoking. Our replication dataset was derived from the genome-wide association study (GWAS) of the FECD Genetics Consortium, where genotypes for three of 10 mtDNA markers were available. Replication analyses were performed to compare non-Duke cases to all GWAS controls (GWAS1, N = 3200), and to non-Duke controls (GWAS2, N = 3043).The variant A10398G was significantly associated with FECD (odds ratio [OR] = 0.72; 95% confidence interval [CI] = [0.53, 0.98]; P = 0.034), and remains significant after adjusting for smoking status (min P = 0.012). This variant was replicated in GWAS1 (P = 0.019) and GWAS2 (P = 0.036). Haplogroup I was significantly associated with FECD (OR = 0.46; 95% CI = [0.22, 0.97]; P = 0.041) and remains significant after adjusting for the effect of smoking (min P = 0.008) or rs613872 (P = 0.034).The 10398G allele and Haplogroup I appear to confer significant protective effects for FECD. The effect of A10398G and Haplogroup I to FECD is likely independent of the known TCF4 variant. More data are needed to decipher the interaction between smoking and mtDNA haplogroups.

Authors
Li, Y-J; Minear, MA; Qin, X; Rimmler, J; Hauser, MA; Allingham, RR; Igo, RP; Lass, JH; Iyengar, SK; Klintworth, GK; Afshari, NA; Gregory, SG; FECD Genetics Consortium,
MLA Citation
Li, Y-J, Minear, MA, Qin, X, Rimmler, J, Hauser, MA, Allingham, RR, Igo, RP, Lass, JH, Iyengar, SK, Klintworth, GK, Afshari, NA, Gregory, SG, and FECD Genetics Consortium, . "Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy." Investigative ophthalmology & visual science 55.7 (June 10, 2014): 4577-4584.
PMID
24917144
Source
epmc
Published In
Investigative Ophthalmology and Visual Science
Volume
55
Issue
7
Publish Date
2014
Start Page
4577
End Page
4584
DOI
10.1167/iovs.13-13517

Urinary fumonisin B1 and estimated fumonisin intake in women from high- and low-exposure communities in Guatemala.

SCOPE: Fumonisin (FB) intake can be high when maize is a dietary staple. We determined (i) urinary FB (UFB) in women consuming maize in high- and low-exposure communities in Guatemala, (ii) the FB levels in maize, (iii) the relationship between UFB and FB intake, and (iv) the relative excretion of UFB1 , UFB2 , and UFB3 . METHODS AND RESULTS: Urine and maize were analyzed for FB for 1 year in three departments. Maize consumption was estimated by an interview questionnaire. Fumonisin B1 , B2 , and B3 (FB1 , FB2 and FB3 ), were detected in 100% of maize samples. FB1 in maize and urine was significantly higher in Jutiapa compared to Chimaltenango or Escuintla. The FB intake paralleled UFB1 in a dose-dependent manner but UFB1 was present in much higher levels than UFB2 or UFB3 compared to maize. CONCLUSION: In Jutiapa, agroecological conditions favored FB production. UFB1 mirrored the estimated FB intake. UFB1 > 0.1 ng/mL resulted in a dose-dependent increase in the risk of exceeding FB intake of 2 μg/kg b.w./day compared to women with no detectable UFB1 . More than 50% exceeded 2 μg/kg b.w./day when UFB1 was >0.5 ng/mL. UFB2 and UFB3 were rarely detected confirming that FB1 is either absorbed better or preferentially excreted in urine.

Authors
Torres, O; Matute, J; Gelineau-van Waes, J; Maddox, JR; Gregory, SG; Ashley-Koch, AE; Showker, JL; Zitomer, NC; Voss, KA; Riley, RT
MLA Citation
Torres, O, Matute, J, Gelineau-van Waes, J, Maddox, JR, Gregory, SG, Ashley-Koch, AE, Showker, JL, Zitomer, NC, Voss, KA, and Riley, RT. "Urinary fumonisin B1 and estimated fumonisin intake in women from high- and low-exposure communities in Guatemala." Mol Nutr Food Res 58.5 (May 2014): 973-983.
PMID
24375966
Source
pubmed
Published In
Molecular Nutrition & Food Research
Volume
58
Issue
5
Publish Date
2014
Start Page
973
End Page
983
DOI
10.1002/mnfr.201300481

Association of autism with induced or augmented childbirth.

Authors
Miranda, ML; Anthopolos, R; Gregory, SG
MLA Citation
Miranda, ML, Anthopolos, R, and Gregory, SG. "Association of autism with induced or augmented childbirth." Am J Obstet Gynecol 210.5 (May 2014): 492-493. (Letter)
PMID
24380745
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
210
Issue
5
Publish Date
2014
Start Page
492
End Page
493
DOI
10.1016/j.ajog.2013.12.038

OMICS PROFILING HIGHLIGHTS ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION AND UBIQUITIN PROTEASOME PATHWAYS IN INSULIN RESISTANCE AND GLYCEMIC CONTROL

Authors
McGarrah, R; Craig, DM; Haynes, C; Hauser, E; Newgard, CB; Gregory, SG; Kraus, W; Shah, S
MLA Citation
McGarrah, R, Craig, DM, Haynes, C, Hauser, E, Newgard, CB, Gregory, SG, Kraus, W, and Shah, S. "OMICS PROFILING HIGHLIGHTS ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION AND UBIQUITIN PROTEASOME PATHWAYS IN INSULIN RESISTANCE AND GLYCEMIC CONTROL." Journal of the American College of Cardiology 63.12 (April 2014): A1600-A1600.
Source
crossref
Published In
JACC - Journal of the American College of Cardiology
Volume
63
Issue
12
Publish Date
2014
Start Page
A1600
End Page
A1600
DOI
10.1016/S0735-1097(14)61603-X

Genetic predisposition of behavioral response.

Authors
Gregory, SG
MLA Citation
Gregory, SG. "Genetic predisposition of behavioral response." Proceedings of the National Academy of Sciences of the United States of America 111.5 (February 2014): 1672-1673.
PMID
24449895
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
5
Publish Date
2014
Start Page
1672
End Page
1673
DOI
10.1073/pnas.1323421111

Induction or augmentation of labor and autism--reply.

Authors
Miranda, ML; Anthopolos, R; Gregory, SG
MLA Citation
Miranda, ML, Anthopolos, R, and Gregory, SG. "Induction or augmentation of labor and autism--reply." JAMA pediatrics 168.2 (February 2014): 191-192. (Letter)
PMID
24492875
Source
epmc
Published In
JAMA Pediatrics
Volume
168
Issue
2
Publish Date
2014
Start Page
191
End Page
192
DOI
10.1001/jamapediatrics.2013.4792

Association of autism with induced or augmented childbirth

Authors
Miranda, ML; Anthopolos, R; Gregory, SG
MLA Citation
Miranda, ML, Anthopolos, R, and Gregory, SG. "Association of autism with induced or augmented childbirth." American Journal of Obstetrics and Gynecology 210.5 (January 1, 2014): 492-493. (Letter)
Source
scopus
Published In
American Journal of Obstetrics & Gynecology
Volume
210
Issue
5
Publish Date
2014
Start Page
492
End Page
493
DOI
10.1016/j.ajog.2013.12.038

The epigenetics of Autism-Running beyond the bases

© 2014 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. Previous studies have established that there is a strong genetic component to the development of ASD, but these genetic risks do not account for all of the heritability of the disorder. This raises the prospect that alternative, epigenetic mechanisms may play a role in ASD development. Epigenetic mechanisms facilitate temporal and spatial regulation of gene expression, but are independent of changes to the underlying DNA sequence. Because epigenetic profi les are labile, they represent an intriguing mechanism whereby environmental infl uences, which are not severe enough to alter the DNA sequence of a cell, may alter gene expression and cellular response and contribute to ASD. In this chapter, we discuss the role of DNA methylation and histone modifi cations in the development of ASD.

Authors
Gregory, SG
MLA Citation
Gregory, SG. "The epigenetics of Autism-Running beyond the bases." Frontiers in Autism Research: New Horizons for Diagnosis and Treatment. January 1, 2014. 303-333.
Source
scopus
Publish Date
2014
Start Page
303
End Page
333
DOI
10.1142/9789814602167_0013

Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10(-3) ) and 22 (LOD = 3.45, p = 6 × 10(-5) ) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.

Authors
Markunas, CA; Enterline, DS; Dunlap, K; Soldano, K; Cope, H; Stajich, J; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
MLA Citation
Markunas, CA, Enterline, DS, Dunlap, K, Soldano, K, Cope, H, Stajich, J, Grant, G, Fuchs, H, Gregory, SG, and Ashley-Koch, AE. "Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation." Ann Hum Genet 78.1 (January 2014): 1-12.
PMID
24359474
Source
pubmed
Published In
Annals of Human Genetics
Volume
78
Issue
1
Publish Date
2014
Start Page
1
End Page
12
DOI
10.1111/ahg.12041

Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990–1998) and Education Research (1997–2007) Databases

Authors
Gregory, SG; Anthopolos, R; Osgood, CE; Grotegut, CA; Miranda, ML
MLA Citation
Gregory, SG, Anthopolos, R, Osgood, CE, Grotegut, CA, and Miranda, ML. "Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990–1998) and Education Research (1997–2007) Databases." Obstetrical & Gynecological Survey 69.1 (January 2014): 7-9.
Source
crossref
Published In
Obstetrical and Gynecological Survey
Volume
69
Issue
1
Publish Date
2014
Start Page
7
End Page
9
DOI
10.1097/01.ogx.0000442814.50107.fa

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmedor stochastic nature of hypomethylation, identifyingthesechanges is important in understanding vascular disease,asmaintenance ofacells' epigenetic profile is essential for maintaining cellularphenotype. Global hypomethylation of proliferating aorticSMCsandconcomitant decrease ofDNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P 5 0.017, OR 5 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease. © The Author 2013.

Authors
Connelly, JJ; Cherepanova, OA; Doss, JF; Karaoli, T; Lillard, TS; Markunas, CA; Nelson, S; Wang, T; Ellis, PD; Langford, CF; Haynes, C; Seo, DM; Goldschmidt-Clermont, PJ; Shah, SH; Kraus, WE; Hauser, ER; Gregory, SG
MLA Citation
Connelly, JJ, Cherepanova, OA, Doss, JF, Karaoli, T, Lillard, TS, Markunas, CA, Nelson, S, Wang, T, Ellis, PD, Langford, CF, Haynes, C, Seo, DM, Goldschmidt-Clermont, PJ, Shah, SH, Kraus, WE, Hauser, ER, and Gregory, SG. "Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis." Human Molecular Genetics 22.25 (December 1, 2013): 5107-5120.
PMID
23912340
Source
scopus
Published In
Human Molecular Genetics
Volume
22
Issue
25
Publish Date
2013
Start Page
5107
End Page
5120
DOI
10.1093/hmg/ddt365

Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

We performed a gene-smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene-smoking interaction at P < 0.05 using association in the presence of linkage--ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene-smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher's combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.

Authors
Ward-Caviness, C; Haynes, C; Blach, C; Dowdy, E; Gregory, SG; Shah, SH; Horne, BD; Kraus, WE; Hauser, ER
MLA Citation
Ward-Caviness, C, Haynes, C, Blach, C, Dowdy, E, Gregory, SG, Shah, SH, Horne, BD, Kraus, WE, and Hauser, ER. "Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort." Hum Genet 132.12 (December 2013): 1371-1382.
PMID
23907653
Source
pubmed
Published In
Human Genetics
Volume
132
Issue
12
Publish Date
2013
Start Page
1371
End Page
1382
DOI
10.1007/s00439-013-1339-7

Rare Variants Identified With Whole Exome Chip Genotyping Are Associated With Insulin Resistance and Glycemic Control

Authors
Shah, SH; Kwee, L; Stitziel, N; Hauser, ER; Haynes, C; Kathiresan, S; Gregory, SG; Kraus, WE
MLA Citation
Shah, SH, Kwee, L, Stitziel, N, Hauser, ER, Haynes, C, Kathiresan, S, Gregory, SG, and Kraus, WE. "Rare Variants Identified With Whole Exome Chip Genotyping Are Associated With Insulin Resistance and Glycemic Control." November 26, 2013.
Source
wos-lite
Published In
Circulation
Volume
128
Issue
22
Publish Date
2013

Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes.

Authors
Soldano, KL; Garrett, ME; Cope, HL; Rusnak, JM; Ellis, NJ; Dunlap, KL; Speer, MC; Gregory, SG; Ashley-Koch, AE
MLA Citation
Soldano, KL, Garrett, ME, Cope, HL, Rusnak, JM, Ellis, NJ, Dunlap, KL, Speer, MC, Gregory, SG, and Ashley-Koch, AE. "Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype." Birth Defects Res B Dev Reprod Toxicol 98.5 (October 2013): 365-373.
PMID
24323870
Source
pubmed
Published In
Birth Defects Research Part B: Developmental and Reproductive Toxicology
Volume
98
Issue
5
Publish Date
2013
Start Page
365
End Page
373
DOI
10.1002/bdrb.21079

Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases.

IMPORTANCE: One in 88 children in the United States is diagnosed as having autism spectrum disorder. Significant interest centers on understanding the environmental factors that may contribute to autism risk. OBJECTIVE: To examine whether induced (stimulating uterine contractions prior to the onset of spontaneous labor) and/or augmented (increasing the strength, duration, or frequency of uterine contractions with spontaneous onset of labor) births are associated with increased odds of autism. DESIGN, SETTING, AND PARTICIPANTS: We performed an epidemiological analysis using multivariable logistic regression modeling involving the North Carolina Detailed Birth Record and Education Research databases. The study featured 625,042 live births linked with school records, including more than 5500 children with a documented exceptionality designation for autism. EXPOSURES: Induced or augmented births. MAIN OUTCOMES AND MEASURES: Autism as assessed by exceptionality designations in child educational records. RESULTS: Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children. CONCLUSIONS AND RELEVANCE: Our work suggests that induction/augmentation during childbirth is associated with increased odds of autism diagnosis in childhood. While these results are interesting, further investigation is needed to differentiate among potential explanations of the association including underlying pregnancy conditions requiring the eventual need to induce/augment, the events of labor and delivery associated with induction/augmentation, and the specific treatments and dosing used to induce/augment labor (e.g., exogenous oxytocin and prostaglandins).

Authors
Gregory, SG; Anthopolos, R; Osgood, CE; Grotegut, CA; Miranda, ML
MLA Citation
Gregory, SG, Anthopolos, R, Osgood, CE, Grotegut, CA, and Miranda, ML. "Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases." JAMA Pediatr 167.10 (October 2013): 959-966.
PMID
23938610
Source
pubmed
Published In
JAMA Pediatrics
Volume
167
Issue
10
Publish Date
2013
Start Page
959
End Page
966
DOI
10.1001/jamapediatrics.2013.2904

Interactions between Social/behavioral factors and ADRB2 genotypes may be associated with health at advanced ages in China

Authors
Zeng, Y; Cheng, L; Zhao, L; Tan, Q; Feng, Q; Chen, H; Shen, K; Li, J; Zhang, F; Cao, H; Gregory, SG; Yang, Z; Gu, J; Tao, W; Tian, X-L; Hauser, ER
MLA Citation
Zeng, Y, Cheng, L, Zhao, L, Tan, Q, Feng, Q, Chen, H, Shen, K, Li, J, Zhang, F, Cao, H, Gregory, SG, Yang, Z, Gu, J, Tao, W, Tian, X-L, and Hauser, ER. "Interactions between Social/behavioral factors and ADRB2 genotypes may be associated with health at advanced ages in China." BMC GERIATRICS 13 (September 9, 2013).
Website
http://hdl.handle.net/10161/15374
PMID
24016068
Source
wos-lite
Published In
BMC Geriatrics
Volume
13
Publish Date
2013
DOI
10.1186/1471-2318-13-91

Association of Gene Expression Signatures with Small Molecule Metabolic Intermediates that Predict Cardiovascular Mortality in CATHGEN

Authors
Kraus, WE; Feng, S; Hauser, ER; Gregory, SG; Haynes, C; Dowdy, ZE; Craig, DM; Shah, SH
MLA Citation
Kraus, WE, Feng, S, Hauser, ER, Gregory, SG, Haynes, C, Dowdy, ZE, Craig, DM, and Shah, SH. "Association of Gene Expression Signatures with Small Molecule Metabolic Intermediates that Predict Cardiovascular Mortality in CATHGEN." March 26, 2013.
Source
wos-lite
Published In
Circulation
Volume
127
Issue
12
Publish Date
2013

Genetics of the Chiari i and II malformationsGenetics of the Chiari i and II malformations

© 2013 Springer Science+Business Media New York. All rights reserved. Chiari malformations are considered to have a multifactorial etiology, likely influenced by environmental and genetic factors. This chapter will detail the evidence that supports a genetic contribution to the disorder, including discussions of twin studies, familial aggregation, co-occurrence with known genetic syndromes, and previous genetic studies. While no susceptibility genes have been identified to date, gene identification efforts are continuing. It is expected that researchers will have a more complete understanding of the specific genes and biological pathways that contribute to disease development in the coming years. The future benefits from genetic research of Chiari I and II may include the development of genetic tests that result in more accurate and faster diagnoses as well as new targeted treatment options for patients.

Authors
Markunas, CA; Ashley-Koch, AE; Gregory, SG; Markunas, CA; Ashley-Koch, AE; Gregory, SG
MLA Citation
Markunas, CA, Ashley-Koch, AE, Gregory, SG, Markunas, CA, Ashley-Koch, AE, and Gregory, SG. "Genetics of the Chiari i and II malformationsGenetics of the Chiari i and II malformations (PublishedPublished)." The Chiari Malformations. March 1, 2013. 93-101.
Source
scopus
Volume
9781461463696
Publish Date
2013
Start Page
93
End Page
101
DOI
10.1007/978-1-4614-6369-6_7

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6.

Interleukin 7 receptor, IL7R, is expressed exclusively on cells of the lymphoid lineage, and its expression is crucial for the development and maintenance of T cells. Alternative splicing of IL7R exon 6 results in membrane-bound (exon 6 included) and soluble (exon 6 skipped) IL7R isoforms. Interestingly, the inclusion of exon 6 is affected by a single-nucleotide polymorphism associated with the risk of developing multiple sclerosis. Given the potential association of exon 6 inclusion with multiple sclerosis, we investigated the cis-acting elements and trans-acting factors that regulate exon 6 splicing. We identified multiple exonic and intronic cis-acting elements that impact inclusion of exon 6. Moreover, we utilized RNA affinity chromatography followed by mass spectrometry to identify trans-acting protein factors that bind exon 6 and regulate its splicing. These experiments identified cleavage and polyadenylation specificity factor 1 (CPSF1) among protein-binding candidates. A consensus polyadenylation signal AAUAAA is present in intron 6 of IL7R directly downstream from the 5' splice site. Mutations to this site and CPSF1 knockdown both resulted in an increase in exon 6 inclusion. We found no evidence that this site is used to produce cleaved and polyadenylated mRNAs, suggesting that CPSF1 interaction with intronic IL7R pre-mRNA interferes with spliceosome binding to the exon 6 5' splice site. Our results suggest that competing mRNA splicing and polyadenylation regulate exon 6 inclusion and consequently determine the ratios of soluble to membrane-bound IL7R. This may be relevant for both T cell ontogeny and function and development of multiple sclerosis.

Authors
Evsyukova, I; Bradrick, SS; Gregory, SG; Garcia-Blanco, MA
MLA Citation
Evsyukova, I, Bradrick, SS, Gregory, SG, and Garcia-Blanco, MA. "Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6." RNA 19.1 (January 2013): 103-115.
PMID
23151878
Source
pubmed
Published In
RNA (New York, N.Y.)
Volume
19
Issue
1
Publish Date
2013
Start Page
103
End Page
115
DOI
10.1261/rna.035410.112

Genetic screen of African Americans with Fuchs endothelial corneal dystrophy.

PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. METHODS: Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. RESULTS: Twenty-two coding variants were detected across the COL8A2, SLC4A11, and ZEB1 genes; six were nonsynonymous variants. Three novel coding variants were detected: a synonymous variant each in COL8A2 and SLC4A11 and one nonsynonymous variant in ZEB1 (p.P559S), which is predicted to be benign and tolerated, thus making its physiologic consequence uncertain. CONCLUSIONS: Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans. This observation is on par with findings from previous sequencing studies involving European or Asian ancestry patients with FECD.

Authors
Minear, MA; Li, Y-J; Rimmler, J; Balajonda, E; Watson, S; Allingham, RR; Hauser, MA; Klintworth, GK; Afshari, NA; Gregory, SG
MLA Citation
Minear, MA, Li, Y-J, Rimmler, J, Balajonda, E, Watson, S, Allingham, RR, Hauser, MA, Klintworth, GK, Afshari, NA, and Gregory, SG. "Genetic screen of African Americans with Fuchs endothelial corneal dystrophy. (Published online)" Mol Vis 19 (2013): 2508-2516.
PMID
24348007
Source
pubmed
Published In
Molecular vision
Volume
19
Publish Date
2013
Start Page
2508
End Page
2516

Outcome and life satisfaction of adults with myelomeningocele

Background: Myelomeningocele (MMC) commonly causes impairments in body structure and functions as well as cognitive disabilities that can have an adverse effect on adult life. Improved medical care has resulted in increased numbers of individuals with MMC surviving to adulthood, however little is known about the impact of MMC on the lives of adults age 25 years or older. Objective: To gain a better understanding of outcomes in education, employment, relationships, reproduction and life satisfaction of adults with MMC. Methods: A primarily quantitative multiple-choice questionnaire designed to capture outcomes in education, employment, relationships and reproduction, along with a previously validated life satisfaction checklist (LiSat-11), was completed by adults with MMC. Relationships between demographic variables, outcomes and life satisfaction were determined using cross tabulation analysis, logistic regression and linear regression. Results: Ninety adults with MMC, age 25-85 years (median age 32), reported a diverse range of outcomes in education, employment, relationships and reproduction. The most consistent variable associated with difficulty attaining adult milestones was hydrocephalus, the presence of which reduced the likelihood of living independently (p ≤ 0.001), having a partner (p = 0.003) and reproducing (p ≤ 0.001), but did not contribute to reduced life satisfaction. Conclusions: Adults with MMC, especially those without hydrocephalus, can obtain gainful employment, live independently, form partner relationships and have children, and these achievements contribute to life satisfaction. While MMC does not affect overall reported life satisfaction for adults, attention should be paid to specific domains with less reported satisfaction. © 2013 Elsevier Inc. All rights reserved.

Authors
Cope, H; McMahon, K; Heise, E; Eubanks, S; Garrett, M; Gregory, S; Ashley-Koch, A
MLA Citation
Cope, H, McMahon, K, Heise, E, Eubanks, S, Garrett, M, Gregory, S, and Ashley-Koch, A. "Outcome and life satisfaction of adults with myelomeningocele." Disability and Health Journal (2013).
PMID
23769483
Source
scival
Published In
Disability and Health Journal
Publish Date
2013
DOI
10.1016/j.dhjo.2012.12.003

Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Authors
Markunas, CA; Soldano, K; Dunlap, K; Cope, H; Asiimwe, E; Stajich, J; Enterline, D; Grant, G; Fuchs, H; Gregory, SG; Ashley-Koch, AE
MLA Citation
Markunas, CA, Soldano, K, Dunlap, K, Cope, H, Asiimwe, E, Stajich, J, Enterline, D, Grant, G, Fuchs, H, Gregory, SG, and Ashley-Koch, AE. "Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. (Published online)" PLoS One 8.4 (2013): e61521-.
PMID
23620759
Source
pubmed
Published In
PloS one
Volume
8
Issue
4
Publish Date
2013
Start Page
e61521
DOI
10.1371/journal.pone.0061521

Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family.

Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09-0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ≥ 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk.

Authors
Nolan, D; Kraus, WE; Hauser, E; Li, Y-J; Thompson, DK; Johnson, J; Chen, H-C; Nelson, S; Haynes, C; Gregory, SG; Kraus, VB; Shah, SH
MLA Citation
Nolan, D, Kraus, WE, Hauser, E, Li, Y-J, Thompson, DK, Johnson, J, Chen, H-C, Nelson, S, Haynes, C, Gregory, SG, Kraus, VB, and Shah, SH. "Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family. (Published online)" PLoS One 8.8 (2013): e71779-.
Website
http://hdl.handle.net/10161/10873
PMID
23936524
Source
pubmed
Published In
PloS one
Volume
8
Issue
8
Publish Date
2013
Start Page
e71779
DOI
10.1371/journal.pone.0071779

Integration of Whole Genome Methylation with Metabolomics Identifies Novel Cardiovascular Disease Genes

Authors
Shah, SH; Feng, S; Grass, E; Haynes, C; Chryst-Ladd, M; Craig, D; Hauser, ER; Newgard, CB; Kraus, WE; Gregory, SG
MLA Citation
Shah, SH, Feng, S, Grass, E, Haynes, C, Chryst-Ladd, M, Craig, D, Hauser, ER, Newgard, CB, Kraus, WE, and Gregory, SG. "Integration of Whole Genome Methylation with Metabolomics Identifies Novel Cardiovascular Disease Genes." CIRCULATION 126.21 (November 20, 2012).
Source
wos-lite
Published In
Circulation
Volume
126
Issue
21
Publish Date
2012

Genetic Variants in the Bone Morphogenic Protein (BMP) Family of Genes Interact with Mobile Source Air Pollution to Increase Risk of Peripheral Arterial Disease

Authors
Ward-Caviness, C; Neas, L; Haynes, C; Blach, C; Burns, E; LaRocque-Abramson, K; Dowdy, E; Casco, W; Devlin, R; Diaz-Sanchez, D; Kraus, WE; Shah, SH; Gregory, SG; Miranda, ML; Hauser, ER
MLA Citation
Ward-Caviness, C, Neas, L, Haynes, C, Blach, C, Burns, E, LaRocque-Abramson, K, Dowdy, E, Casco, W, Devlin, R, Diaz-Sanchez, D, Kraus, WE, Shah, SH, Gregory, SG, Miranda, ML, and Hauser, ER. "Genetic Variants in the Bone Morphogenic Protein (BMP) Family of Genes Interact with Mobile Source Air Pollution to Increase Risk of Peripheral Arterial Disease." CIRCULATION 126.21 (November 20, 2012).
Source
wos-lite
Published In
Circulation
Volume
126
Issue
21
Publish Date
2012

Transcriptome profiling of genes involved in neural tube closure during human embryonic development using long serial analysis of gene expression (long-SAGE).

BACKGROUND: Neural tube defects (NTDs) are common human birth defects with a complex etiology. To develop a comprehensive knowledge of the genes expressed during normal neurulation, we established transcriptomes from human neural tube fragments during and after neurulation using long Serial Analysis of Gene Expression (long-SAGE). METHODS: Rostral and caudal neural tubes were dissected from normal human embryos aged between 26 and 32 days of gestation. Tissues from the same region and Carnegie stage were pooled (n ≥ 4) and total RNA extracted to construct four long-SAGE libraries. Tags were mapped using the UniGene Homo sapiens 17 bp tag-to-gene best mapping set. Differentially expressed genes were identified by chi-square or Fisher's exact test, and validation was performed for a subset of those transcripts using in situ hybridization. In silico analyses were performed with BinGO and EXPANDER. RESULTS: We observed most genes to be similarly regulated in rostral and caudal regions, but expression profiles differed during and after closure. In silico analysis found similar enrichments in both regions for biologic process terms, transcription factor binding and miRNA target motifs. Twelve genes potentially expressing alternate isoforms by region or developmental stage, and the microRNAs miR-339-5p, miR-141/200a, miR-23ab, and miR-129/129-5p are among several potential candidates identified here for future research. CONCLUSIONS: Time appears to influence gene expression in the developing central nervous system more than location. These data provide a novel complement to traditional strategies of identifying genes associated with human NTDs and offer unique insight into the genes associated with normal human neurulation.

Authors
Krupp, DR; Xu, P-T; Thomas, S; Dellinger, A; Etchevers, HC; Vekemans, M; Gilbert, JR; Speer, MC; Ashley-Koch, AE; Gregory, SG; National Birth Defects Prevention Study,
MLA Citation
Krupp, DR, Xu, P-T, Thomas, S, Dellinger, A, Etchevers, HC, Vekemans, M, Gilbert, JR, Speer, MC, Ashley-Koch, AE, Gregory, SG, and National Birth Defects Prevention Study, . "Transcriptome profiling of genes involved in neural tube closure during human embryonic development using long serial analysis of gene expression (long-SAGE)." Birth Defects Res A Clin Mol Teratol 94.9 (September 2012): 683-692.
PMID
22806986
Source
pubmed
Published In
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume
94
Issue
9
Publish Date
2012
Start Page
683
End Page
692
DOI
10.1002/bdra.23040

The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets.

SCOPE: Fumonisins (FB) are mycotoxins found in maize. The purpose of this study was to (i) determine the relationship between FB(1) , FB(2) , and FB(3) intake and urinary excretion in humans, (ii) validate a method to isolate urinary FB on C(18) -SPE cartridges for international shipment, and (iii) test the method using samples from Guatemala. METHODS AND RESULTS: Volunteers (n = 10) consumed 206 grams/day of tortillas and biscuits prepared from masa flour and a product containing maize flour. Volunteers estimated their daily urine output and samples were analyzed for FB(1) , FB(2) , and FB(3) and hydrolyzed FB(1) . Only FB(1) was detected in urine suggesting lower absorption of FB(2) and FB(3) . Excretion was highly variable peaking soon after consumption began and decreasing rapidly after consumption stopped. Within 5 days after consumption ended, FB(1) was not detected in urine. In a study with eight volunteers, the average total urinary FB(1) was 0.5% of the intake. FB(1) was detected in 61% (107/177) of the samples collected in Guatemala. CONCLUSION: The results support the use of urinary FB(1) to assess ongoing exposure in population-based studies. However, relating the FB(1) concentration in urine to dietary intake of FB by individual subjects will be complicated due to interindividual variability and the rapidity of clearance.

Authors
Riley, RT; Torres, O; Showker, JL; Zitomer, NC; Matute, J; Voss, KA; Gelineau-van Waes, J; Maddox, JR; Gregory, SG; Ashley-Koch, AE
MLA Citation
Riley, RT, Torres, O, Showker, JL, Zitomer, NC, Matute, J, Voss, KA, Gelineau-van Waes, J, Maddox, JR, Gregory, SG, and Ashley-Koch, AE. "The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets." Mol Nutr Food Res 56.9 (September 2012): 1445-1455.
PMID
22815244
Source
pubmed
Published In
Molecular Nutrition & Food Research
Volume
56
Issue
9
Publish Date
2012
Start Page
1445
End Page
1455
DOI
10.1002/mnfr.201200166

Clinical, radiological, and genetic similarities between patients with Chiari Type I and Type 0 malformations.

OBJECT: Although Chiari Type I (CM-I) and Type 0 (CM-0) malformations have been previously characterized clinically and radiologically, there have been no studies focusing on the possible genetic link between these disorders. The goal of this study was to identify families in whom CM-0 and CM-I co-occurred and to further assess the similarities between these disorders. METHODS: Families were ascertained through a proband with CM-I. Detailed family histories were obtained to identify first-degree relatives diagnosed with CM-0. Several criteria were used to exclude individuals with acquired forms of CM-I and/or syringomyelia. Individuals were excluded with syndromic, traumatic, infectious, or tumor-related syringomyelia, as well as CM-I due to a supratentorial mass, hydrocephalus, history of cervical or cranial surgery unrelated to CM-I, or development of symptoms following placement of a lumbar shunt. Medical records and MR images were used to characterize CM-I and CM-0 individuals clinically and radiologically. RESULTS: Five families were identified in which the CM-I proband had a first-degree relative with CM-0. Further assessment of affected individuals showed similar clinical and radiological features between CM-0 and CM-I individuals, although CM-I patients in general had more severe symptoms and skull base abnormalities than their CM-0 relatives. Overall, both groups showed improvement in symptoms and/or syrinx size following craniocervical decompression surgery. CONCLUSIONS: There is accumulating evidence suggesting that CM-0 and CM-I may be caused by a common underlying developmental mechanism. The data in this study are consistent with this hypothesis, showing similar clinical and radiological features between CM-0 and CM-I individuals, as well as the occurrence of both disorders within families. Familial clustering of CM-0 and CM-I suggests that these disorders may share an underlying genetic basis, although additional epigenetic and/or environmental factors are likely to play an important role in the development of CM-0 versus CM-I.

Authors
Markunas, CA; Tubbs, RS; Moftakhar, R; Ashley-Koch, AE; Gregory, SG; Oakes, WJ; Speer, MC; Iskandar, BJ
MLA Citation
Markunas, CA, Tubbs, RS, Moftakhar, R, Ashley-Koch, AE, Gregory, SG, Oakes, WJ, Speer, MC, and Iskandar, BJ. "Clinical, radiological, and genetic similarities between patients with Chiari Type I and Type 0 malformations." J Neurosurg Pediatr 9.4 (April 2012): 372-378.
PMID
22462700
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
9
Issue
4
Publish Date
2012
Start Page
372
End Page
378
DOI
10.3171/2011.12.PEDS11113

Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5.

BACKGROUND: Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT; GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aortas). RESULTS: We identified four genes with SNPs that showed the strongest and most consistent associations with LDL-C and CAD: EBF1, PPP2R2B, SPOCK1, and PRELID2. The most significant results for association of SNPs with LDL-C were: EBF1, rs6865969, p = 0.01; PPP2R2B, rs2125443, p = 0.005; SPOCK1, rs17600115, p = 0.003; and PRELID2, rs10074645, p = 0.0002). The most significant results for CAD were EBF1, rs6865969, p = 0.007; PPP2R2B, rs7736604, p = 0.0003; SPOCK1, rs17170899, p = 0.004; and PRELID2, rs7713855, p = 0.003. CONCLUSION: Using an intermediate disease-related quantitative trait of LDL-C we have identified four novel CAD genes, EBF1, PRELID2, SPOCK1, and PPP2R2B. These four genes should be further examined in future functional studies as candidate susceptibility loci for cardiovascular disease mediated through LDL-cholesterol pathways.

Authors
Nolan, DK; Sutton, B; Haynes, C; Johnson, J; Sebek, J; Dowdy, E; Crosslin, D; Crossman, D; Sketch, MH; Granger, CB; Seo, D; Goldschmidt-Clermont, P; Kraus, WE; Gregory, SG; Hauser, ER; Shah, SH
MLA Citation
Nolan, DK, Sutton, B, Haynes, C, Johnson, J, Sebek, J, Dowdy, E, Crosslin, D, Crossman, D, Sketch, MH, Granger, CB, Seo, D, Goldschmidt-Clermont, P, Kraus, WE, Gregory, SG, Hauser, ER, and Shah, SH. "Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5. (Published online)" BMC Genet 13 (February 27, 2012): 12-.
PMID
22369142
Source
pubmed
Published In
BMC Genetics
Volume
13
Publish Date
2012
Start Page
12
DOI
10.1186/1471-2156-13-12

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors.

Authors
Lin, N; Di, C; Bortoff, K; Fu, J; Truszkowski, P; Killela, P; Duncan, C; McLendon, R; Bigner, D; Gregory, S; Adamson, DC
MLA Citation
Lin, N, Di, C, Bortoff, K, Fu, J, Truszkowski, P, Killela, P, Duncan, C, McLendon, R, Bigner, D, Gregory, S, and Adamson, DC. "Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma." Mol Cancer Res 10.2 (February 2012): 208-217.
PMID
22241217
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
10
Issue
2
Publish Date
2012
Start Page
208
End Page
217
DOI
10.1158/1541-7786.MCR-10-0109

Genome-Wide Association Identifies Genetic Variants Associated With Vein Graft Stenosis After Coronary Artery Bypass Grafting

Authors
Shah, AA; Craig, DM; Haynes, C; Sebek, JK; Grass, E; Abramson, K; Smith, PK; Hauser, ER; Gregory, SG; Kraus, WE; Shah, SH
MLA Citation
Shah, AA, Craig, DM, Haynes, C, Sebek, JK, Grass, E, Abramson, K, Smith, PK, Hauser, ER, Gregory, SG, Kraus, WE, and Shah, SH. "Genome-Wide Association Identifies Genetic Variants Associated With Vein Graft Stenosis After Coronary Artery Bypass Grafting." November 22, 2011.
Source
wos-lite
Published In
Circulation
Volume
124
Issue
21
Publish Date
2011

Genomic Rearrangements in Autism: The Contribution of Copy Number Loss and Gain to the Etiology of Autism Spectrum Disorders.

Authors
Gregory, SG
MLA Citation
Gregory, SG. "Genomic Rearrangements in Autism: The Contribution of Copy Number Loss and Gain to the Etiology of Autism Spectrum Disorders." October 2011. S17-S17.
Source
wos-lite
Volume
52
Publish Date
2011
Start Page
S17
End Page
S17

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.

The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs-PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.

Authors
Hara, MR; Kovacs, JJ; Whalen, EJ; Rajagopal, S; Strachan, RT; Grant, W; Towers, AJ; Williams, B; Lam, CM; Xiao, K; Shenoy, SK; Gregory, SG; Ahn, S; Duckett, DR; Lefkowitz, RJ
MLA Citation
Hara, MR, Kovacs, JJ, Whalen, EJ, Rajagopal, S, Strachan, RT, Grant, W, Towers, AJ, Williams, B, Lam, CM, Xiao, K, Shenoy, SK, Gregory, SG, Ahn, S, Duckett, DR, and Lefkowitz, RJ. "A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. (Published online)" Nature 477.7364 (August 21, 2011): 349-353.
PMID
21857681
Source
pubmed
Published In
Nature
Volume
477
Issue
7364
Publish Date
2011
Start Page
349
End Page
353
DOI
10.1038/nature10368

Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease.

Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10(-6) and 5 × 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.

Authors
Minear, MA; Crosslin, DR; Sutton, BS; Connelly, JJ; Nelson, SC; Gadson-Watson, S; Wang, T; Seo, D; Vance, JM; Sketch, MH; Haynes, C; Goldschmidt-Clermont, PJ; Shah, SH; Kraus, WE; Hauser, ER; Gregory, SG
MLA Citation
Minear, MA, Crosslin, DR, Sutton, BS, Connelly, JJ, Nelson, SC, Gadson-Watson, S, Wang, T, Seo, D, Vance, JM, Sketch, MH, Haynes, C, Goldschmidt-Clermont, PJ, Shah, SH, Kraus, WE, Hauser, ER, and Gregory, SG. "Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease." Hum Genet 129.6 (June 2011): 641-654.
PMID
21298289
Source
pubmed
Published In
Human Genetics
Volume
129
Issue
6
Publish Date
2011
Start Page
641
End Page
654
DOI
10.1007/s00439-011-0959-z

Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10(-35); ADD: P = 7.48×10(-30); REC: P = 5.27×10(-6)). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

Authors
Li, Y-J; Minear, MA; Rimmler, J; Zhao, B; Balajonda, E; Hauser, MA; Allingham, RR; Eghrari, AO; Riazuddin, SA; Katsanis, N; Gottsch, JD; Gregory, SG; Klintworth, GK; Afshari, NA
MLA Citation
Li, Y-J, Minear, MA, Rimmler, J, Zhao, B, Balajonda, E, Hauser, MA, Allingham, RR, Eghrari, AO, Riazuddin, SA, Katsanis, N, Gottsch, JD, Gregory, SG, Klintworth, GK, and Afshari, NA. "Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. (Published online)" PLoS One 6.4 (April 20, 2011): e18044-.
PMID
21533127
Source
pubmed
Published In
PloS one
Volume
6
Issue
4
Publish Date
2011
Start Page
e18044
DOI
10.1371/journal.pone.0018044

The S1103Y cardiac sodium channel variant is associated with implantable cardioverter-defibrillator events in blacks with heart failure and reduced ejection fraction.

BACKGROUND: Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel SCN5A variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction. METHODS AND RESULTS: Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%, P=0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73, P=<0.01). There was no difference in mortality between carriers and noncarriers. CONCLUSIONS: This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.

Authors
Sun, AY; Koontz, JI; Shah, SH; Piccini, JP; Nilsson, KR; Craig, D; Haynes, C; Gregory, SG; Hranitzky, PM; Pitt, GS
MLA Citation
Sun, AY, Koontz, JI, Shah, SH, Piccini, JP, Nilsson, KR, Craig, D, Haynes, C, Gregory, SG, Hranitzky, PM, and Pitt, GS. "The S1103Y cardiac sodium channel variant is associated with implantable cardioverter-defibrillator events in blacks with heart failure and reduced ejection fraction." Circ Cardiovasc Genet 4.2 (April 2011): 163-168.
PMID
21498565
Source
pubmed
Published In
Circulation: Cardiovascular Genetics
Volume
4
Issue
2
Publish Date
2011
Start Page
163
End Page
168
DOI
10.1161/CIRCGENETICS.110.958652

Association of mtDNA haplogroup F with healthy longevity in the female Chuang population, China

Human longevity is a complex heritable genetic trait. Based on substantial evidence from model organisms, it is clear that mitochondria play a pivotal role in aging and lifespan. However, the effects that mitochondrial genome variations have upon longevity and longevity-related phenotypes in Chuang people in China have yet to be established. By genotyping 15 variants for 10 haplogroups in 738 Chuang subjects, including 367 long-lived individuals and 371 controls, we found that haplogroup F was significantly associated with longevity in females of Zhuang population of China (p = 0.003, OR: 2.01, 95%CI: 1.263-3.197). Additionally, haplogroup F was related to higher HDL levels (p < 0.05) in long-lived individuals. Further analysis suggests that the non-synonymous variant m.13928G>C in haplogroup F was also associated with longevity in female Zhuang Chinese which might account for the beneficial effect of F. © 2011 Elsevier Inc.

Authors
Feng, J; Zhang, J; Liu, M; Wan, G; Qi, K; Zheng, C; Lv, Z; Hu, C; Zeng, Y; Gregory, SG; Yang, Z
MLA Citation
Feng, J, Zhang, J, Liu, M, Wan, G, Qi, K, Zheng, C, Lv, Z, Hu, C, Zeng, Y, Gregory, SG, and Yang, Z. "Association of mtDNA haplogroup F with healthy longevity in the female Chuang population, China." Experimental Gerontology 46.12 (2011): 987-993.
PMID
21945877
Source
scival
Published In
Experimental Gerontology
Volume
46
Issue
12
Publish Date
2011
Start Page
987
End Page
993
DOI
10.1016/j.exger.2011.09.001

HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.

Authors
Jin, G; Cook, S; Cui, B; Chen, WC; Keir, ST; Killela, P; Di, C; Payne, CA; Gregory, SG; McLendon, R; Bigner, DD; Yan, H
MLA Citation
Jin, G, Cook, S, Cui, B, Chen, WC, Keir, ST, Killela, P, Di, C, Payne, CA, Gregory, SG, McLendon, R, Bigner, DD, and Yan, H. "HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea." Neuro Oncol 12.9 (September 2010): 956-966.
PMID
20472715
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
9
Publish Date
2010
Start Page
956
End Page
966
DOI
10.1093/neuonc/noq045

Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.

The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

Authors
Duncan, CG; Killela, PJ; Payne, CA; Lampson, B; Chen, WC; Liu, J; Solomon, D; Waldman, T; Towers, AJ; Gregory, SG; McDonald, KL; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Duncan, CG, Killela, PJ, Payne, CA, Lampson, B, Chen, WC, Liu, J, Solomon, D, Waldman, T, Towers, AJ, Gregory, SG, McDonald, KL, McLendon, RE, Bigner, DD, and Yan, H. "Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes." Oncotarget 1.4 (August 2010): 265-277.
PMID
21113414
Source
pubmed
Published In
Oncotarget
Volume
1
Issue
4
Publish Date
2010
Start Page
265
End Page
277
DOI
10.18632/oncotarget.137

Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies.

Aging is believed to be among the most important contributors to atherosclerosis, through mechanisms that remain largely obscure. Serum levels of tumor necrosis factor (TNF) rise with aging and have been correlated with the incidence of myocardial infarction. We therefore sought to determine whether genetic variation in the TNF receptor-1 gene (TNFR1) contributes to aging-related atherosclerosis in humans and whether Tnfr1 expression aggravates aging-related atherosclerosis in mice. With 1330 subjects from a coronary angiography database, we performed a case-control association study of coronary artery disease (CAD) with 16 TNFR1 single-nucleotide polymorphisms (SNPs). Two TNFR1 SNPs significantly associated with CAD in subjects >55 years old, and this association was supported by analysis of a set of 759 independent CAD cases. In multiple linear regression analysis, accounting for TNFR1 SNP rs4149573 significantly altered the relationship between aging and CAD index among 1811 subjects from the coronary angiography database. To confirm that TNFR1 contributes to aging-dependent atherosclerosis, we grafted carotid arteries from 18- and 2-month-old wild-type (WT) and Tnfr1(-/-) mice into congenic apolipoprotein E-deficient (Apoe(-/-)) mice and harvested grafts from 1 to 7 weeks post-operatively. Aged WT arteries developed accelerated atherosclerosis associated with enhanced TNFR1 expression, enhanced macrophage recruitment, reduced smooth muscle cell proliferation and collagen content, augmented apoptosis and plaque hemorrhage. In contrast, aged Tnfr1(-/-) arteries developed atherosclerosis that was indistinguishable from that in young Tnfr1(-/-) arteries and significantly less than that observed in aged WT arteries. We conclude that TNFR1 polymorphisms associate with aging-related CAD in humans, and TNFR1 contributes to aging-dependent atherosclerosis in mice.

Authors
Zhang, L; Connelly, JJ; Peppel, K; Brian, L; Shah, SH; Nelson, S; Crosslin, DR; Wang, T; Allen, A; Kraus, WE; Gregory, SG; Hauser, ER; Freedman, NJ
MLA Citation
Zhang, L, Connelly, JJ, Peppel, K, Brian, L, Shah, SH, Nelson, S, Crosslin, DR, Wang, T, Allen, A, Kraus, WE, Gregory, SG, Hauser, ER, and Freedman, NJ. "Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies." Hum Mol Genet 19.14 (July 15, 2010): 2754-2766.
PMID
20421368
Source
pubmed
Published In
Human Molecular Genetics
Volume
19
Issue
14
Publish Date
2010
Start Page
2754
End Page
2766
DOI
10.1093/hmg/ddq172

Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses.

We studied the status of chromosomes 1 and 19 in 363 astrocytic and oligodendroglial tumors. Whereas the predominant pattern of copy number abnormality was a concurrent loss of the entire 1p and 19q regions (total 1p/19q loss) among oligodendroglial tumors and partial deletions of 1p and/or 19q in astrocytic tumors, a subset of apparently astrocytic tumors also had total 1p/19q loss. The presence of total 1p/19q loss was associated with longer survival of patients with all types of adult gliomas independent of age and diagnosis (P = .041). The most commonly deleted region on 19q in astrocytic tumors spans 885 kb in 19q13.33-q13.41, which is telomeric to the previously proposed region. Novel regions of homozygous deletion, including a part of DPYD (1p21.3) or the KLK cluster (19q13.33), were observed in anaplastic oligodendrogliomas. Amplifications encompassing AKT2 (19q13.2) or CCNE1 (19q12) were identified in some glioblastomas. Deletion mapping of the centromeric regions of 1p and 19q in the tumors that had total 1p/19q loss, indicating that the breakpoints lie centromeric to NOTCH2 within the pericentromeric regions of 1p and 19q. Thus, we show that the copy number abnormalities of 1p and 19q in human gliomas are complex and have distinct patterns that are prognostically predictive independent of age and pathological diagnosis. An accurate identification of total 1p/19q loss and discriminating this from other 1p/19q changes is, however, critical when the 1p/19q copy number status is used to stratify patients in clinical trials.

Authors
Vogazianou, AP; Chan, R; Bäcklund, LM; Pearson, DM; Liu, L; Langford, CF; Gregory, SG; Collins, VP; Ichimura, K
MLA Citation
Vogazianou, AP, Chan, R, Bäcklund, LM, Pearson, DM, Liu, L, Langford, CF, Gregory, SG, Collins, VP, and Ichimura, K. "Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses." Neuro Oncol 12.7 (July 2010): 664-678.
PMID
20164239
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
7
Publish Date
2010
Start Page
664
End Page
678
DOI
10.1093/neuonc/nop075

Alternative splicing in multiple sclerosis and other autoimmune diseases.

Alternative splicing is a general mechanism for regulating gene expression that affects the RNA products of more than 90% of human genes. Not surprisingly, alternative splicing is observed among gene products of metazoan immune systems, which have evolved to efficiently recognize pathogens and discriminate between "self" and "non-self", and thus need to be both diverse and flexible. In this review we focus on the specific interface between alternative splicing and autoimmune diseases, which result from a malfunctioning of the immune system and are characterized by the inappropriate reaction to self-antigens. Despite the widespread recognition of alternative splicing as one of the major regulators of gene expression, the connections between alternative splicing and autoimmunity have not been apparent. We summarize recent findings connecting splicing and autoimmune disease, and attempt to find common patterns of splicing regulation that may advance our understanding of autoimmune diseases and open new avenues for therapy.

Authors
Evsyukova, I; Somarelli, JA; Gregory, SG; Garcia-Blanco, MA
MLA Citation
Evsyukova, I, Somarelli, JA, Gregory, SG, and Garcia-Blanco, MA. "Alternative splicing in multiple sclerosis and other autoimmune diseases." RNA Biol 7.4 (July 2010): 462-473. (Review)
Website
http://hdl.handle.net/10161/3963
PMID
20639696
Source
pubmed
Published In
RNA biology
Volume
7
Issue
4
Publish Date
2010
Start Page
462
End Page
473

Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene.

We have used the public sequencing and annotation of the mouse genome to delimit the previously resolved type 1 diabetes (T1D) insulin-dependent diabetes (Idd)18 interval to a region on chromosome 3 that includes the immunologically relevant candidate gene, Vav3. To test the candidacy of Vav3, we developed a novel congenic strain that enabled the resolution of Idd18 to a 604-kb interval, designated Idd18.1, which contains only two annotated genes: the complete sequence of Vav3 and the last exon of the gene encoding NETRIN G1, Ntng1. Targeted sequencing of Idd18.1 in the NOD mouse strain revealed that allelic variation between NOD and C57BL/6J (B6) occurs in noncoding regions with 138 single nucleotide polymorphisms concentrated in the introns between exons 20 and 27 and immediately after the 3' untranslated region. We observed differential expression of VAV3 RNA transcripts in thymocytes when comparing congenic mouse strains with B6 or NOD alleles at Idd18.1. The T1D protection associated with B6 alleles of Idd18.1/Vav3 requires the presence of B6 protective alleles at Idd3, which are correlated with increased IL-2 production and regulatory T cell function. In the absence of B6 protective alleles at Idd3, we detected a second T1D protective B6 locus, Idd18.3, which is closely linked to, but distinct from, Idd18.1. Therefore, genetic mapping, sequencing, and gene expression evidence indicate that alteration of VAV3 expression is an etiological factor in the development of autoimmune beta-cell destruction in NOD mice. This study also demonstrates that a congenic strain mapping approach can isolate closely linked susceptibility genes.

Authors
Fraser, HI; Dendrou, CA; Healy, B; Rainbow, DB; Howlett, S; Smink, LJ; Gregory, S; Steward, CA; Todd, JA; Peterson, LB; Wicker, LS
MLA Citation
Fraser, HI, Dendrou, CA, Healy, B, Rainbow, DB, Howlett, S, Smink, LJ, Gregory, S, Steward, CA, Todd, JA, Peterson, LB, and Wicker, LS. "Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene." J Immunol 184.9 (May 1, 2010): 5075-5084.
PMID
20363978
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
184
Issue
9
Publish Date
2010
Start Page
5075
End Page
5084
DOI
10.4049/jimmunol.0903734

Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family.

OBJECTIVE: The genetic contributions to the multifactorial disorder osteoarthritis (OA) have been increasingly recognized. The goal of the current study was to use OA-related biomarkers of severity and disease burden as quantitative traits to identify genetic susceptibility loci for OA. METHODS: In a large multigenerational extended family (n = 350), we measured 5 OA-related biomarkers: hyaluronan (HA), cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA collagen (PIIANP), C-propeptide of type II procollagen (CPII), and type II collagen neoepitope (C2C). Single-nucleotide polymorphism markers (n = 6,090) covering the whole genome were genotyped using the Illumina HumanLinkage-12 BeadChip. Variance components analysis, as implemented in the Sequential Oligogenic Linkage Analysis Routines, was used to estimate heritabilities of the quantitative traits and to calculate 2-point and multipoint logarithm of odds (LOD) scores using a polygenic model. RESULTS: After adjusting for age and sex, we found that 4 of the 5 biomarkers exhibited significant heritability (PIIANP 0.57, HA 0.49, COMP 0.43, C2C 0.30; P < or = 0.01 for all). Fourteen of the 19 loci that had multipoint LOD scores of >1.5 were near to or overlapped with previously reported OA susceptibility loci. Four of these loci were identified by more than 1 biomarker. The maximum multipoint LOD scores for the heritable quantitative biomarker traits were 4.3 for PIIANP (chromosome 8p23.2), 3.2 for COMP (chromosome 8q11.1), 2.0 for HA (chromosome 6q16.3), and 2.0 for C2C (chromosome 5q31.2). CONCLUSION: Herein, we report the first evidence of genetic susceptibility loci identified by OA-related biomarkers in an extended family. Our results demonstrate that serum concentrations of PIIANP, HA, COMP, and C2C have substantial heritable components, and using these biomarkers, several genetic loci potentially contributing to the genetic diversity of OA were identified.

Authors
Chen, H-C; Kraus, VB; Li, Y-J; Nelson, S; Haynes, C; Johnson, J; Stabler, T; Hauser, ER; Gregory, SG; Kraus, WE; Shah, SH
MLA Citation
Chen, H-C, Kraus, VB, Li, Y-J, Nelson, S, Haynes, C, Johnson, J, Stabler, T, Hauser, ER, Gregory, SG, Kraus, WE, and Shah, SH. "Genome-wide linkage analysis of quantitative biomarker traits of osteoarthritis in a large, multigenerational extended family." Arthritis Rheum 62.3 (March 2010): 781-790.
PMID
20187133
Source
pubmed
Published In
Arthritis and Rheumatism
Volume
62
Issue
3
Publish Date
2010
Start Page
781
End Page
790
DOI
10.1002/art.27288

Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Authors
Riazuddin, SA; Zaghloul, NA; Al-Saif, A; Davey, L; Diplas, BH; Meadows, DN; Eghrari, AO; Minear, MA; Li, Y-J; Klintworth, GK; Afshari, N; Gregory, SG; Gottsch, JD; Katsanis, N
MLA Citation
Riazuddin, SA, Zaghloul, NA, Al-Saif, A, Davey, L, Diplas, BH, Meadows, DN, Eghrari, AO, Minear, MA, Li, Y-J, Klintworth, GK, Afshari, N, Gregory, SG, Gottsch, JD, and Katsanis, N. "Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p." Am J Hum Genet 86.1 (January 2010): 45-53.
PMID
20036349
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
86
Issue
1
Publish Date
2010
Start Page
45
End Page
53
DOI
10.1016/j.ajhg.2009.12.001

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.

BACKGROUND: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. METHODS: We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). RESULTS: Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. CONCLUSION: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63.

Authors
Gregory, SG; Connelly, JJ; Towers, AJ; Johnson, J; Biscocho, D; Markunas, CA; Lintas, C; Abramson, RK; Wright, HH; Ellis, P; Langford, CF; Worley, G; Delong, GR; Murphy, SK; Cuccaro, ML; Persico, A; Pericak-Vance, MA
MLA Citation
Gregory, SG, Connelly, JJ, Towers, AJ, Johnson, J, Biscocho, D, Markunas, CA, Lintas, C, Abramson, RK, Wright, HH, Ellis, P, Langford, CF, Worley, G, Delong, GR, Murphy, SK, Cuccaro, ML, Persico, A, and Pericak-Vance, MA. "Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. (Published online)" BMC Med 7 (October 22, 2009): 62-.
PMID
19845972
Source
pubmed
Published In
BMC Medicine
Volume
7
Publish Date
2009
Start Page
62
DOI
10.1186/1741-7015-7-62

Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease affecting >4,00,000 individuals in the United States. Population and family-based studies have suggested that there is a strong genetic component. Numerous genomic linkage screens have identified regions of interest for MS loci. Our own second-generation genome-wide linkage study identified a handful of non-major histocompatibility complex regions with suggestive linkage. Several of these regions were further examined using single-nucleotide polymorphisms (SNPs) with average spacing between SNPs of approximately 1.0 Mb in a dataset of 173 multiplex families. The results of that study provided further evidence for the involvement of the chromosome 1q43 region. This region is of particular interest given linkage evidence in studies of other autoimmune and inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus. In this follow-up study, we saturated the region with approximately 700 SNPs (average spacing of 10 kb per SNP) in search of disease-associated variation within this region. We found preliminary evidence to suggest that common variation within the RGS7 locus may be involved in disease susceptibility.

Authors
McCauley, JL; Zuvich, RL; Bradford, Y; Kenealy, SJ; Schnetz-Boutaud, N; Gregory, SG; Hauser, SL; Oksenberg, JR; Mortlock, DP; Pericak-Vance, MA; Haines, JL
MLA Citation
McCauley, JL, Zuvich, RL, Bradford, Y, Kenealy, SJ, Schnetz-Boutaud, N, Gregory, SG, Hauser, SL, Oksenberg, JR, Mortlock, DP, Pericak-Vance, MA, and Haines, JL. "Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis." Genes Immun 10.7 (October 2009): 624-630.
PMID
19626040
Source
pubmed
Published In
Genes & Immunity
Volume
10
Issue
7
Publish Date
2009
Start Page
624
End Page
630
DOI
10.1038/gene.2009.53

A general integrative genomic feature transcription factor binding site prediction method applied to analysis of USF1 binding in cardiovascular disease.

Transcription factors are key mediators of human complex disease processes. Identifying the target genes of transcription factors will increase our understanding of the biological network leading to disease risk. The prediction of transcription factor binding sites (TFBSs) is one method to identify these target genes; however, current prediction methods need improvement. We chose the transcription factor upstream stimulatory factor 1 ( USF1 ) to evaluate the performance of our novel TFBS prediction method because of its known genetic association with coronary artery disease (CAD) and the recent availability of USF1 chromatin immunoprecipitation microarray (ChIP-chip) results. The specific goals of our study were to develop a novel and accurate genome-scale method for predicting USF1 binding sites and associated target genes to aid in the study of CAD. Previously published USF1 ChIP-chip data for 1 per cent of the genome were used to develop and evaluate several kernel logistic regression prediction models. A combination of genomic features (phylogenetic conservation, regulatory potential, presence of a CpG island and DNaseI hypersensitivity), as well as position weight matrix (PWM) scores, were used as variables for these models. Our most accurate predictor achieved an area under the receiver operator characteristic curve of 0.827 during cross-validation experiments, significantly outperforming standard PWM-based prediction methods. When applied to the whole human genome, we predicted 24,010 USF1 binding sites within 5 kilobases upstream of the transcription start site of 9,721 genes. These predictions included 16 of 20 genes with strong evidence of USF1 regulation. Finally, in the spirit of genomic convergence, we integrated independent experimental CAD data with these USF1 binding site prediction results to develop a prioritised set of candidate genes for future CAD studies. We have shown that our novel prediction method, which employs genomic features related to the presence of regulatory elements, enables more accurate and efficient prediction of USF1 binding sites. This method can be extended to other transcription factors identified in human disease studies to help further our understanding of the biology of complex disease.

Authors
Wang, T; Furey, TS; Connelly, JJ; Ji, S; Nelson, S; Heber, S; Gregory, SG; Hauser, ER
MLA Citation
Wang, T, Furey, TS, Connelly, JJ, Ji, S, Nelson, S, Heber, S, Gregory, SG, and Hauser, ER. "A general integrative genomic feature transcription factor binding site prediction method applied to analysis of USF1 binding in cardiovascular disease." Hum Genomics 3.3 (April 2009): 221-235.
PMID
19403457
Source
pubmed
Published In
Human genomics
Volume
3
Issue
3
Publish Date
2009
Start Page
221
End Page
235

Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis.

Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility.

Authors
Crosslin, DR; Shah, SH; Nelson, SC; Haynes, CS; Connelly, JJ; Gadson, S; Goldschmidt-Clermont, PJ; Vance, JM; Rose, J; Granger, CB; Seo, D; Gregory, SG; Kraus, WE; Hauser, ER
MLA Citation
Crosslin, DR, Shah, SH, Nelson, SC, Haynes, CS, Connelly, JJ, Gadson, S, Goldschmidt-Clermont, PJ, Vance, JM, Rose, J, Granger, CB, Seo, D, Gregory, SG, Kraus, WE, and Hauser, ER. "Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis." Hum Genet 125.2 (March 2009): 217-229.
PMID
19130089
Source
pubmed
Published In
Human Genetics
Volume
125
Issue
2
Publish Date
2009
Start Page
217
End Page
229
DOI
10.1007/s00439-008-0619-0

Genome-wide linkage scan in fuchs endothelial corneal dystrophy.

PURPOSE: To perform a genome-wide linkage screen with a single-nucleotide polymorphism (SNP) linkage panel to identify regions of genetic linkage in Fuchs endothelial corneal dystrophy (FECD) and to analyze affected individuals for mutations in the COL8A2 gene. METHODS: Ninety-two individuals from 22 families with FECD were identified from our multiplex FECD family cohort. A genome-wide linkage scan was performed using an SNP linkage panel. Parametric two-point linkage analyses were calculated and nonparametric multipoint linkage analyses were performed on chromosomes with two-point LOD scores (HLOD) > 1.0. All affected individuals were analyzed for the two previously reported FECD mutations in the COL8A2 gene (L450W and Q455K). RESULTS: The genome-wide analysis identified five regions with linkage signals from all analyses on chromosomes 1, 7, 15, 17, and X. The highest two-point HLODs were found on the long arm of chromosome 15 with an HLOD of 3.26 for the recessive model and 2.48 for the dominant model. Multipoint linkage analysis also identified a linkage peak on the long arm of chromosome 15 with a LOD > 1. The region of linkage on chromosome 1p, driven by two multigenerational FECD families with a two-point LOD > 2, was adjacent to the previously identified COL8A2 gene; however, the two reported mutations in COL8A2 were not identified in any of the 56 affected individuals in the 92 samples tested. CONCLUSIONS: Genome-wide linkage analysis was used to identify potential linkage regions on chromosomes 1, 7, 15, 17, and X for FECD. The previously reported mutations in the COL8A2 gene were not found in the 92 samples tested.

Authors
Afshari, NA; Li, Y-J; Pericak-Vance, MA; Gregory, S; Klintworth, GK
MLA Citation
Afshari, NA, Li, Y-J, Pericak-Vance, MA, Gregory, S, and Klintworth, GK. "Genome-wide linkage scan in fuchs endothelial corneal dystrophy." Invest Ophthalmol Vis Sci 50.3 (March 2009): 1093-1097.
PMID
18502986
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
50
Issue
3
Publish Date
2009
Start Page
1093
End Page
1097
DOI
10.1167/iovs.08-1839

Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.

Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.

Authors
Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJH; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt-Clermont, PJ; Kraus, WE; Hauser, ER
MLA Citation
Shah, SH, Freedman, NJ, Zhang, L, Crosslin, DR, Stone, DH, Haynes, C, Johnson, J, Nelson, S, Wang, L, Connelly, JJ, Muehlbauer, M, Ginsburg, GS, Crossman, DC, Jones, CJH, Vance, J, Sketch, MH, Granger, CB, Newgard, CB, Gregory, SG, Goldschmidt-Clermont, PJ, Kraus, WE, and Hauser, ER. "Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis." PLoS Genet 5.1 (January 2009): e1000318-.
Website
http://hdl.handle.net/10161/16064
PMID
19119412
Source
pubmed
Published In
PLoS genetics
Volume
5
Issue
1
Publish Date
2009
Start Page
e1000318
DOI
10.1371/journal.pgen.1000318

IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels. © 2009 Maier et al.

Authors
Maier, LM; Lowe, CE; Cooper, J; Downes, K; Anderson, DE; Severson, C; Clark, PM; Healy, B; Walker, N; Aubin, C; Oksenberg, JR; Hauser, SL; Compston, A; Sawcer, S; Jager, PLD; Wicker, LS; Todd, JA; Hafler, DA; Daly, MJ; Bakker, PIWD; Gabriel, SB; Mirel, DB; Ivinson, AJ; Pericak-Vance, MA; Gregory, SG; Rioux, JD; McCauley, JL; Haines, JL; Barcellos, LF
MLA Citation
Maier, LM, Lowe, CE, Cooper, J, Downes, K, Anderson, DE, Severson, C, Clark, PM, Healy, B, Walker, N, Aubin, C, Oksenberg, JR, Hauser, SL, Compston, A, Sawcer, S, Jager, PLD, Wicker, LS, Todd, JA, Hafler, DA, Daly, MJ, Bakker, PIWD, Gabriel, SB, Mirel, DB, Ivinson, AJ, Pericak-Vance, MA, Gregory, SG, Rioux, JD, McCauley, JL, Haines, JL, and Barcellos, LF. "IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production." PLoS Genetics 5.1 (2009).
PMID
19119414
Source
scival
Published In
PLoS genetics
Volume
5
Issue
1
Publish Date
2009
DOI
10.1371/journal.pgen.1000322

Mapping techniques

In 1920, German botanist Hans Winkler first used the term genome, reputedly by the fusion of GENe and chromosOME, in order to describe the complex notion of the entire set of chromosomes and all of the genes contained within an organism. A great deal of progress has since been made in the elucidation of the complex molecular interactions that underlie cellular functioning and the syntenic relationship between organisms at a nucleotide level. The basis for these advances was the characterization of the structure of DNA by Watson and Crick in 1953 (1) and the realization that DNA could be decoded to provide a guide to genetic inheritance. This underpinned the concept of genetics and provided scientists with the opportunity to explore and quantify the nature and extent of the biological information passed on from one generation to the next. The characterization of biological inheritance permitted the elucidation of what it was that was being encoded and how it could determine biochemical function. Finally, extending from elucidation of the mechanisms behind inheritance of monogenic diseases, scientists are beginning to grasp how sequence is also involved in complex interactions, occasionally under the influence of environmental factors, to contribute to many (but still not all) diseases. The speed at which the vast amount of human sequence data were generated can be attributed to the evolution of strategies and techniques developed to map and sequence organisms such as bacteria (2) yeast (3) and the nematode worm (4) The availability of such an evolutionary diverse collection of species, with the addition of the mouse (5) and other complex multicellular organisms, has also enabled comparisons to be made at a nucleotide level. The first genomes that were characterized were relatively small by current standards, bacteriophage ?X174, 5 kb (6,7) and bacteriophage ?, 48 kb (8) - but they provided the underlying techniques and strategies that are being used for the more complex organisms currently being studied. Chain termination sequencing, developed by Sanger (8) is a synthetic method in which nested sets of labeled fragments are generated in vitro by a DNA polymerase reaction. Because the method is highly sensitive and robust, it has been amenable to biochemical optimization, producing long, accurate sequence reads, and also to automation, which was necessary for large-scale application of the technique. In these respects, it differed from the method of Maxam and Gilbert (9) which necessitated production of all of the labeled material prior to chemical degradation to form the sequence ladders of nested fragments. As a result, the Sanger method has remained the technique by which the majority of genomic sequence from a variety of complex organisms is presently being generated (see Fig. 20.1). However, neither method is capable of generating single reads of greater than 2-300 nucleotides, limited in part by the sequence production itself and partly by the ability to separate the sequence by gel electrophoresis at single-base resolution (even today, sequencing read lengths approaching 1 kb are rare). The assembly of larger tracts of DNA therefore required the development of methods to reassemble a consensus sequence from multiple individual reads. Two approaches were adopted for this; first, the construction of physical maps of restriction fragments using sequence-specific restriction enzymes to order and orienta te large segments of DNA from which individual units were selected for sequencing; second, the use of the information gained from each individual sequence read to order and orient each segment relative to overlapping neighbors, which required the development of advanced computer programs to make the task possible on all but the smallest scale. A further modification of the latter was made by Anderson (10) who developed the random shotgun strategy to elucidate the mitochondrial genome, involved using a random fragmentation process by partial DNAse I digestion (11). This removed the dependence on sequence-specific restriction enzymes while still relying on sequence-based assembly of contiguous tracts of overlapping reads. The random shotgun approach, in which genomic DNA is randomly sequenced in similarly sized segments and then assembled simultaneously to provide a representation of the genomic template, provided the basis of the strategies used to assemble sequences of large inserts cloned inplasmids, lambda phage, and cosmid vectors (12), and also the later bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) clones (13). The same random shotgun strategy was adopted to sequence the 1.8-Mb genome of the bacterium Haemophilus influenzae (14). Although the whole-genome shotgun sequencing approach has proven itself to be a successful strategy for the rapid assembly of smaller genomes, there are doubts as to whether this strategy is suitable for assembling the sequence of complex organisms. The generation of a physical map, in which the genome is divided into bacterial clone units of 40-200 kb and assembled into contiguous stretches (contigs) of overlapping clones, is a process analogous to the sequence contig assembly process. In contrast to sequence assembly, however, the information used to compare individual clones and identify overlaps of a physical map (e.g., the Caenorhabditis elegans (4) and Saccharomyces cerevisiae (3) genome projects) use a one-dimensional fingerprint prepared by separating restriction fragments from a limit digest of each cloned DNA by electrophoresis. Overlaps between clones were detected on the basis of partially (or completely) shared fingerprint patterns. An alternative approach to identify overlapping relationships between clones was to test clones for the presence of characterized markers. Overlaps between clones could be identified on the basis that they shared a single copy sequence. The presence of the sequence was identified using a specific hybridization probe or polymerase chain reaction (PCR) assay. Given a physical map of overlapping clones, individual clones can then be selected from the map to provide maximum genomic coverage with minimal redundancy. These clones permit specific regions to be targeted for further investigation and, in particular, for the determination of the complete DNA sequence separately from other clones within the physical map. Because the source of the genomic sequence is limited to an individual clone, problems encountered with sequence assemblies are greatly reduced compared to the corresponding whole-genome assemblies. At the time of their inception, the physical maps of the C. elegans (4) and S. cerevisiae (3) genomes were constructed to enhance the molecular genetics of the respective organisms by facilitating the cloning of known genes and to serve as an archive for genomic information. However, the data associated with the construction of the clonal physical maps-even with good alignment to the genetic map-carried only a tiny proportion of information present (16) within the genome. Consequently, a minimum tile path of the 30-kb cosmid and 15-kb lambda clones, used to build the physical maps of the C. elegans and S. cerevisiae, respectively, were subcloned into M13 phage vectors (1.3-2 kb insert size) and sequenced on a per-clone basis. The physical maps of the two genomes (2)(15), and subsequently of Drosophila melanogaster (17), and human (12), used restriction enzyme fragments in various ways to overlap clonal units for the construction of genomewide physical maps. © 2008 Humana Press.

Authors
Gregory, SG
MLA Citation
Gregory, SG. "Mapping techniques." (December 1, 2008): 291-310. (Chapter)
Source
scopus
Publish Date
2008
Start Page
291
End Page
310
DOI
10.1007/978-1-60327-375-6_20

ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention.

BACKGROUND: Use of drug-eluting stents (DES) has reduced in-stent restenosis after percutaneous coronary intervention (PCI); however, DES are associated with late stent thrombosis. There is no accurate way to predict in-stent restenosis, although risk factors for atherosclerosis overlap those for in-stent restenosis. Therefore, we evaluated atherosclerosis candidate genes for association with in-stent restenosis. METHODS: We identified 46 consecutive cases that had undergone PCI with bare-metal stents who subsequently developed symptomatic in-stent restenosis of the target lesion (>/=75% luminal narrowing) within 6 months. Forty-six age-, race-, vessel-diameter- and sex-matched controls without in-stent restenosis after PCI with bare-metal stent were also identified. Single-nucleotide polymorphisms (SNPs, N=82) from 39 candidate atherosclerosis genes were genotyped. Multivariable logistic regression models were used to test for association. RESULTS: Five SNPs were associated with in-stent restenosis. Three ALOX5AP SNPs were most strongly associated, two with increased risk (OR 3.74, p=0.01; OR 3.46, p=0.02), and the third with decreased risk of in-stent restenosis (OR 0.09, p=0.004). Two ALOX5AP haplotypes were associated with in-stent restenosis (HapB: OR 3.13, p=0.03); and a haplotype similar to HapA: OR 0.14, p=0.0009). CONCLUSIONS: ALOX5AP, a gene within the inflammatory leukotriene pathway linked to and associated with coronary atherosclerosis, is also associated with in-stent restenosis. Genotyping these variants may help identify those at risk for in-stent restenosis who would benefit most from use of DES.

Authors
Shah, SH; Hauser, ER; Crosslin, D; Wang, L; Haynes, C; Connelly, J; Nelson, S; Johnson, J; Gadson, S; Nelson, CL; Seo, D; Gregory, S; Kraus, WE; Granger, CB; Goldschmidt-Clermont, P; Newby, LK
MLA Citation
Shah, SH, Hauser, ER, Crosslin, D, Wang, L, Haynes, C, Connelly, J, Nelson, S, Johnson, J, Gadson, S, Nelson, CL, Seo, D, Gregory, S, Kraus, WE, Granger, CB, Goldschmidt-Clermont, P, and Newby, LK. "ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention." Atherosclerosis 201.1 (November 2008): 148-154.
PMID
18374923
Source
pubmed
Published In
Atherosclerosis
Volume
201
Issue
1
Publish Date
2008
Start Page
148
End Page
154
DOI
10.1016/j.atherosclerosis.2008.01.011

Biliverdin Reductase Genetic Polymorphisms are Associated with Early-Onset Coronary Artery Disease In Two Datasets

Authors
Goswami, R; Sutton, BS; Rouf, C; Nelson, S; Haynes, C; Johnson, J; Goldschmidt-Clermont, P; Seo, D; Kraus, WE; Hauser, ER; Gregory, SG; Shah, SS
MLA Citation
Goswami, R, Sutton, BS, Rouf, C, Nelson, S, Haynes, C, Johnson, J, Goldschmidt-Clermont, P, Seo, D, Kraus, WE, Hauser, ER, Gregory, SG, and Shah, SS. "Biliverdin Reductase Genetic Polymorphisms are Associated with Early-Onset Coronary Artery Disease In Two Datasets." CIRCULATION 118.18 (October 28, 2008): S389-S390.
Source
wos-lite
Published In
Circulation
Volume
118
Issue
18
Publish Date
2008
Start Page
S389
End Page
S390

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.

BACKGROUND: Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors. METHODS: We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types. RESULTS: Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04). CONCLUSIONS: Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Authors
Deak, KL; Siegel, DG; George, TM; Gregory, S; Ashley-Koch, A; Speer, MC; NTD Collaborative Group,
MLA Citation
Deak, KL, Siegel, DG, George, TM, Gregory, S, Ashley-Koch, A, Speer, MC, and NTD Collaborative Group, . "Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects." Birth Defects Res A Clin Mol Teratol 82.10 (October 2008): 662-669.
PMID
18937341
Source
pubmed
Published In
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume
82
Issue
10
Publish Date
2008
Start Page
662
End Page
669
DOI
10.1002/bdra.20511

Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease.

Previous association mapping on chromosome 3q13-21 detected evidence for association at the limbic system-associated membrane protein (LSAMP) gene in individuals with late-onset coronary artery disease (CAD). LSAMP has never been implicated in the pathogenesis of CAD. We sought to thoroughly characterize the association and the gene. Non-redundant single nucleotide polymorphisms (SNPs) across the gene were examined in an initial dataset (168 cases with late-onset CAD, 149 controls). Stratification analysis on left main CAD (N = 102) revealed stronger association, which was further validated in a validation dataset (141 cases with left main CAD, 215 controls), a third control dataset (N = 255), and a family-based dataset (N = 2954). A haplotype residing in a novel alternative transcript of the LSAMP gene was significant in all independent case-control datasets (p = 0.0001 to 0.0205) and highly significant in the joint analysis (p = 0.00004). Lower expression of the novel alternative transcript was associated with the risk haplotype (p = 0.0002) and atherosclerosis burden in human aortas (p = 0.0001). Furthermore, silencing LSAMP expression in human aortic smooth muscle cells (SMCs) substantially augmented SMC proliferation (p<0.01). Therefore, the risk conferred by the LSAMP haplotype appears to be mediated by LSAMP down-regulation, which may promote SMC proliferation in the arterial wall and progression of atherosclerosis.

Authors
Wang, L; Hauser, ER; Shah, SH; Seo, D; Sivashanmugam, P; Exum, ST; Gregory, SG; Granger, CB; Haines, JL; Jones, CJH; Crossman, D; Haynes, C; Kraus, WE; Freedman, NJ; Pericak-Vance, MA; Goldschmidt-Clermont, PJ; Vance, JM
MLA Citation
Wang, L, Hauser, ER, Shah, SH, Seo, D, Sivashanmugam, P, Exum, ST, Gregory, SG, Granger, CB, Haines, JL, Jones, CJH, Crossman, D, Haynes, C, Kraus, WE, Freedman, NJ, Pericak-Vance, MA, Goldschmidt-Clermont, PJ, and Vance, JM. "Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease." Ann Hum Genet 72.Pt 4 (July 2008): 443-453.
PMID
18318786
Source
pubmed
Published In
Annals of Human Genetics
Volume
72
Issue
Pt 4
Publish Date
2008
Start Page
443
End Page
453
DOI
10.1111/j.1469-1809.2008.00433.x

Refinement of 2q and 7p loci in a large multiplex NTD family.

BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of approximately 3.0 mapping to 2q33.1-q35 and 7p21.1-pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of approximately 3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1-q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1-21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families.

Authors
Stamm, DS; Siegel, DG; Mehltretter, L; Connelly, JJ; Trott, A; Ellis, N; Zismann, V; Stephan, DA; George, TM; Vekemans, M; Ashley-Koch, A; Gilbert, JR; Gregory, SG; Speer, MC; NTD Collaborative Group,
MLA Citation
Stamm, DS, Siegel, DG, Mehltretter, L, Connelly, JJ, Trott, A, Ellis, N, Zismann, V, Stephan, DA, George, TM, Vekemans, M, Ashley-Koch, A, Gilbert, JR, Gregory, SG, Speer, MC, and NTD Collaborative Group, . "Refinement of 2q and 7p loci in a large multiplex NTD family." Birth Defects Res A Clin Mol Teratol 82.6 (June 2008): 441-452.
PMID
18452155
Source
pubmed
Published In
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume
82
Issue
6
Publish Date
2008
Start Page
441
End Page
452
DOI
10.1002/bdra.20462

Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets

Authors
Sutton, BS; Crosslin, DR; Shah, SH; Nelson, SC; Bassil, A; Hale, AB; Haynes, C; Goldschmidt-Clermont, PJ; Vance, JM; Seo, D; Kraus, WE; Gregory, SG; Hauser, ER
MLA Citation
Sutton, BS, Crosslin, DR, Shah, SH, Nelson, SC, Bassil, A, Hale, AB, Haynes, C, Goldschmidt-Clermont, PJ, Vance, JM, Seo, D, Kraus, WE, Gregory, SG, and Hauser, ER. "Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets." HUMAN MOLECULAR GENETICS 17.9 (May 1, 2008): 1318-1328.
Source
wos-lite
Published In
Human Molecular Genetics
Volume
17
Issue
9
Publish Date
2008
Start Page
1318
End Page
1328
DOI
10.1093/hmg/ddn020

Genetic and functional association of FAM5C with myocardial infarction.

BACKGROUND: We previously identified a 40 Mb region of linkage on chromosome 1q in our early onset coronary artery disease (CAD) genome-wide linkage scan (GENECARD) with modest evidence for linkage (n = 420, LOD 0.95). When the data are stratified by acute coronary syndrome (ACS), this modest maximum in the overall group became a well-defined LOD peak (maximum LOD of 2.17, D1S1589/D1S518). This peak overlaps a recently identified inflammatory biomarker (MCP-1) linkage region from the Framingham Heart Study (maximum LOD of 4.27, D1S1589) and a region of linkage to metabolic syndrome from the IRAS study (maximum LOD of 2.59, D1S1589/D1S518). The overlap of genetic screens in independent data sets provides evidence for the existence of a gene or genes for CAD in this region. METHODS: A peak-wide association screen (457 SNPs) was conducted of a region 1 LOD score down from the peak marker (168-198 Mb) in a linkage peak for acute coronary syndrome (ACS) on chromosome 1, within a family-based early onset coronary artery disease (CAD) sample (GENECARD). RESULTS: Polymorphisms were identified within the 'family with sequence similarity 5, member C' gene (FAM5C) that show genetic linkage to and are associated with myocardial infarction (MI) in GENECARD. The association was confirmed in an independent CAD case-control sample (CATHGEN) and strong association with MI was identified with single nucleotide polymorphisms (SNPs) in the 3' end of FAM5C. FAM5C genotypes were also correlated with expression of the gene in human aorta. Expression levels of FAM5C decreased with increasing passage of proliferating aortic smooth muscle cells (SMC) suggesting a role for this molecule in smooth muscle cell proliferation and senescence. CONCLUSION: These data implicate FAM5C alleles in the risk of myocardial infarction and suggest further functional studies of FAM5C are required to identify the gene's contribution to atherosclerosis.

Authors
Connelly, JJ; Shah, SH; Doss, JF; Gadson, S; Nelson, S; Crosslin, DR; Hale, AB; Lou, X; Wang, T; Haynes, C; Seo, D; Crossman, DC; Mooser, V; Granger, CB; Jones, CJH; Kraus, WE; Hauser, ER; Gregory, SG
MLA Citation
Connelly, JJ, Shah, SH, Doss, JF, Gadson, S, Nelson, S, Crosslin, DR, Hale, AB, Lou, X, Wang, T, Haynes, C, Seo, D, Crossman, DC, Mooser, V, Granger, CB, Jones, CJH, Kraus, WE, Hauser, ER, and Gregory, SG. "Genetic and functional association of FAM5C with myocardial infarction. (Published online)" BMC Med Genet 9 (April 22, 2008): 33-.
PMID
18430236
Source
pubmed
Published In
BMC Medical Genetics
Volume
9
Publish Date
2008
Start Page
33
DOI
10.1186/1471-2350-9-33

1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas.

Astrocytic, oligodendroglial and mixed gliomas are the commonest gliomas in adults. They have distinct phenotypes and clinical courses, but as they exist as a continuous histological spectrum, differentiating them can be difficult. Co-deletions of total 1p and 19q are found in the majority of oligodendrogliomas and considered as a diagnostic marker and a prognostic indicator. The 1p status of astrocytomas has not yet been thoroughly examined. Using a chromosome 1 tile path array, we investigated 108 adult astrocytic tumours for copy number alterations. Total 1p deletions were rare (2%), however partial deletions involving 1p36 were frequently identified in anaplastic astrocytomas (22%) and glioblastomas (34%). Multivariate analysis showed that patients with total 1p deletions had significantly longer survival (P=0.005). In nine glioblastomas homozygous deletions at 1p36 were identified. No somatic mutations were found among the five genes located in the homozygously deleted region. However, the CpG island of TNFRSF9 was hypermethylated in 19% of astrocytic tumours and 87% of glioma cell lines. TNFRSF9 expression was upregulated after demethylation of glioma cell lines. Akt3 amplifications were found in four glioblastomas. Our results indicate that 1p deletions are common anaplastic astrocytomas and glioblastomas but are distinct from the 1p abnormalities in oligodendrogliomas.

Authors
Ichimura, K; Vogazianou, AP; Liu, L; Pearson, DM; Bäcklund, LM; Plant, K; Baird, K; Langford, CF; Gregory, SG; Collins, VP
MLA Citation
Ichimura, K, Vogazianou, AP, Liu, L, Pearson, DM, Bäcklund, LM, Plant, K, Baird, K, Langford, CF, Gregory, SG, and Collins, VP. "1p36 is a preferential target of chromosome 1 deletions in astrocytic tumours and homozygously deleted in a subset of glioblastomas." Oncogene 27.14 (March 27, 2008): 2097-2108.
PMID
17934521
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
27
Issue
14
Publish Date
2008
Start Page
2097
End Page
2108
DOI
10.1038/sj.onc.1210848

A gene expression signature of confinement in peripheral blood of red wolves (Canis rufus)

The stresses that animals experience as a result of modification of their ecological circumstances induce physiological changes that leave a signature in profiles of gene expression. We illustrate this concept in a comparison of free range and confined North American red wolves (Canis rufus). Transcription profiling of peripheral blood samples from 13 red wolf individuals in the Alligator River region of North Carolina revealed a strong signal of differentiation. Four hundred eighty-two out of 2980 transcripts detected on Illumina HumanRef8 oligonucleotide bead arrays were found to differentiate free range and confined wolves at a false discovery rate of 12.8% and P < 0.05. Over-representation of genes in focal adhesion, insulin signalling, proteasomal, and tryptophan metabolism pathways suggests the activation of pro-inflammatory and stress responses in confined animals. Consequently, characterization of differential transcript abundance in an accessible tissue such as peripheral blood identifies biomarkers that could be useful in animal management practices and for evaluating the impact of habitat changes on population health, particularly as attention turns to the impact of climate change on physiology and in turn species distributions. © 2008 The Authors.

Authors
Kennerly, E; Ballmann, A; Martin, S; Wolfinger, R; Gregory, S; Stoskopf, M; Gibson, G
MLA Citation
Kennerly, E, Ballmann, A, Martin, S, Wolfinger, R, Gregory, S, Stoskopf, M, and Gibson, G. "A gene expression signature of confinement in peripheral blood of red wolves (Canis rufus)." Molecular Ecology 17.11 (2008): 2782-2791.
PMID
18466232
Source
scival
Published In
Molecular Ecology
Volume
17
Issue
11
Publish Date
2008
Start Page
2782
End Page
2791
DOI
10.1111/j.1365-294X.2008.03775.x

Genomic convergence identified CAPG and VAMP8 as candidate genes for CAD

Authors
Wang, L; Hauser, ER; Crosslin, D; Nelson, S; Hale, AB; Gregory, SG; Shah, SH; Kraus, WE; Goldschmidt-Clermont, PJ; Vance, JM
MLA Citation
Wang, L, Hauser, ER, Crosslin, D, Nelson, S, Hale, AB, Gregory, SG, Shah, SH, Kraus, WE, Goldschmidt-Clermont, PJ, and Vance, JM. "Genomic convergence identified CAPG and VAMP8 as candidate genes for CAD." October 16, 2007.
Source
wos-lite
Published In
Circulation
Volume
116
Issue
16
Publish Date
2007
Start Page
807
End Page
807

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.

Authors
Gregory, SG; Schmidt, S; Seth, P; Oksenberg, JR; Hart, J; Prokop, A; Caillier, SJ; Ban, M; Goris, A; Barcellos, LF; Lincoln, R; McCauley, JL; Sawcer, SJ; Compston, DAS; Dubois, B; Hauser, SL; Garcia-Blanco, MA; Pericak-Vance, MA; Haines, JL; Multiple Sclerosis Genetics Group,
MLA Citation
Gregory, SG, Schmidt, S, Seth, P, Oksenberg, JR, Hart, J, Prokop, A, Caillier, SJ, Ban, M, Goris, A, Barcellos, LF, Lincoln, R, McCauley, JL, Sawcer, SJ, Compston, DAS, Dubois, B, Hauser, SL, Garcia-Blanco, MA, Pericak-Vance, MA, Haines, JL, and Multiple Sclerosis Genetics Group, . "Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis." Nat Genet 39.9 (September 2007): 1083-1091.
PMID
17660817
Source
pubmed
Published In
Nature Genetics
Volume
39
Issue
9
Publish Date
2007
Start Page
1083
End Page
1091
DOI
10.1038/ng2103

Risk alleles for multiple sclerosis identified by a genomewide study.

BACKGROUND: Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. METHODS: We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. RESULTS: A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). CONCLUSIONS: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

Authors
International Multiple Sclerosis Genetics Consortium, ; Hafler, DA; Compston, A; Sawcer, S; Lander, ES; Daly, MJ; De Jager, PL; de Bakker, PIW; Gabriel, SB; Mirel, DB; Ivinson, AJ; Pericak-Vance, MA; Gregory, SG; Rioux, JD; McCauley, JL; Haines, JL; Barcellos, LF; Cree, B; Oksenberg, JR; Hauser, SL
MLA Citation
International Multiple Sclerosis Genetics Consortium, , Hafler, DA, Compston, A, Sawcer, S, Lander, ES, Daly, MJ, De Jager, PL, de Bakker, PIW, Gabriel, SB, Mirel, DB, Ivinson, AJ, Pericak-Vance, MA, Gregory, SG, Rioux, JD, McCauley, JL, Haines, JL, Barcellos, LF, Cree, B, Oksenberg, JR, and Hauser, SL. "Risk alleles for multiple sclerosis identified by a genomewide study." N Engl J Med 357.9 (August 30, 2007): 851-862.
PMID
17660530
Source
pubmed
Published In
The New England journal of medicine
Volume
357
Issue
9
Publish Date
2007
Start Page
851
End Page
862
DOI
10.1056/NEJMoa073493

SNPs in Multi-species Conserved Sequences (MCS) as useful markers in association studies: a practical approach.

BACKGROUND: Although genes play a key role in many complex diseases, the specific genes involved in most complex diseases remain largely unidentified. Their discovery will hinge on the identification of key sequence variants that are conclusively associated with disease. While much attention has been focused on variants in protein-coding DNA, variants in noncoding regions may also play many important roles in complex disease by altering gene regulation. Since the vast majority of noncoding genomic sequence is of unknown function, this increases the challenge of identifying "functional" variants that cause disease. However, evolutionary conservation can be used as a guide to indicate regions of noncoding or coding DNA that are likely to have biological function, and thus may be more likely to harbor SNP variants with functional consequences. To help bias marker selection in favor of such variants, we devised a process that prioritizes annotated SNPs for genotyping studies based on their location within Multi-species Conserved Sequences (MCSs) and used this process to select SNPs in a region of linkage to a complex disease. This allowed us to evaluate the utility of the chosen SNPs for further association studies. Previously, a region of chromosome 1q43 was linked to Multiple Sclerosis (MS) in a genome-wide screen. We chose annotated SNPs in the region based on location within MCSs (termed MCS-SNPs). We then obtained genotypes for 478 MCS-SNPs in 989 individuals from MS families. RESULTS: Analysis of our MCS-SNP genotypes from the 1q43 region and comparison to HapMap data confirmed that annotated SNPs in MCS regions are frequently polymorphic and show subtle signatures of selective pressure, consistent with previous reports of genome-wide variation in conserved regions. We also present an online tool that allows MCS data to be directly exported to the UCSC genome browser so that MCS-SNPs can be easily identified within genomic regions of interest. CONCLUSION: Our results showed that MCS can easily be used to prioritize markers for follow-up and candidate gene association studies. We believe that this novel approach demonstrates a paradigm for expediting the search for genes contributing to complex diseases.

Authors
McCauley, JL; Kenealy, SJ; Margulies, EH; Schnetz-Boutaud, N; Gregory, SG; Hauser, SL; Oksenberg, JR; Pericak-Vance, MA; Haines, JL; Mortlock, DP
MLA Citation
McCauley, JL, Kenealy, SJ, Margulies, EH, Schnetz-Boutaud, N, Gregory, SG, Hauser, SL, Oksenberg, JR, Pericak-Vance, MA, Haines, JL, and Mortlock, DP. "SNPs in Multi-species Conserved Sequences (MCS) as useful markers in association studies: a practical approach. (Published online)" BMC Genomics 8 (August 6, 2007): 266-.
PMID
17683615
Source
pubmed
Published In
BMC Genomics
Volume
8
Publish Date
2007
Start Page
266
DOI
10.1186/1471-2164-8-266

Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease.

A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13-21 in a linkage study of early-onset CAD. We completed an association-mapping study across the 1-LOD-unit-down supporting interval, using two independent white case-control data sets (CATHGEN, initial and validation) to evaluate association under the peak. Single-nucleotide polymorphisms (SNPs) evenly spaced at 100-kb intervals were screened in the initial data set (N=468). Promising SNPs (P<.1) were then examined in the validation data set (N=514). Significant findings (P<.05) in the combined initial and validation data sets were further evaluated in multiple independent data sets, including a family-based data set (N=2,954), an African American case-control data set (N=190), and an additional white control data set (N=255). The association between genotype and aortic atherosclerosis was examined in 145 human aortas. The peakwide survey found evidence of association in SNPs from multiple genes. The strongest associations were found in three SNPs from the kalirin (KALRN) gene, especially in patients with early-onset CAD (P=.00001-00028 in the combined CATHGEN data sets). In-depth investigation of the gene found that an intronic SNP, rs9289231, was associated with early-onset CAD in all white data sets examined (P<.05). In the joint analysis of all white early-onset CAD cases (N=332) and controls (N=546), rs9289231 was highly significant (P=.00008), with an odds-ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P=.03) in 145 human aortas. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase and guanine-exchange-factor activity. KALRN and two other associated genes identified in this study (CDGAP and MYLK) belong to the Rho GTPase-signaling pathway. Our data suggest the importance of the KALRN gene and the Rho GTPase-signaling pathway in the pathogenesis of CAD.

Authors
Wang, L; Hauser, ER; Shah, SH; Pericak-Vance, MA; Haynes, C; Crosslin, D; Harris, M; Nelson, S; Hale, AB; Granger, CB; Haines, JL; Jones, CJH; Crossman, D; Seo, D; Gregory, SG; Kraus, WE; Goldschmidt-Clermont, PJ; Vance, JM
MLA Citation
Wang, L, Hauser, ER, Shah, SH, Pericak-Vance, MA, Haynes, C, Crosslin, D, Harris, M, Nelson, S, Hale, AB, Granger, CB, Haines, JL, Jones, CJH, Crossman, D, Seo, D, Gregory, SG, Kraus, WE, Goldschmidt-Clermont, PJ, and Vance, JM. "Peakwide mapping on chromosome 3q13 identifies the kalirin gene as a novel candidate gene for coronary artery disease." Am J Hum Genet 80.4 (April 2007): 650-663.
PMID
17357071
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
80
Issue
4
Publish Date
2007
Start Page
650
End Page
663
DOI
10.1086/512981

A second major histocompatibility complex susceptibility locus for multiple sclerosis.

OBJECTIVE: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. METHODS: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. RESULTS: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)). INTERPRETATION: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

Authors
Yeo, TW; De Jager, PL; Gregory, SG; Barcellos, LF; Walton, A; Goris, A; Fenoglio, C; Ban, M; Taylor, CJ; Goodman, RS; Walsh, E; Wolfish, CS; Horton, R; Traherne, J; Beck, S; Trowsdale, J; Caillier, SJ; Ivinson, AJ; Green, T; Pobywajlo, S; Lander, ES; Pericak-Vance, MA; Haines, JL; Daly, MJ; Oksenberg, JR; Hauser, SL; Compston, A; Hafler, DA; Rioux, JD; Sawcer, S
MLA Citation
Yeo, TW, De Jager, PL, Gregory, SG, Barcellos, LF, Walton, A, Goris, A, Fenoglio, C, Ban, M, Taylor, CJ, Goodman, RS, Walsh, E, Wolfish, CS, Horton, R, Traherne, J, Beck, S, Trowsdale, J, Caillier, SJ, Ivinson, AJ, Green, T, Pobywajlo, S, Lander, ES, Pericak-Vance, MA, Haines, JL, Daly, MJ, Oksenberg, JR, Hauser, SL, Compston, A, Hafler, DA, Rioux, JD, and Sawcer, S. "A second major histocompatibility complex susceptibility locus for multiple sclerosis." Ann Neurol 61.3 (March 2007): 228-236.
PMID
17252545
Source
pubmed
Published In
Annals of Neurology
Volume
61
Issue
3
Publish Date
2007
Start Page
228
End Page
236
DOI
10.1002/ana.21063

Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects.

Authors
Motsinger, AA; Brassat, D; Caillier, SJ; Erlich, HA; Walker, K; Steiner, LL; Barcellos, LF; Pericak-Vance, MA; Schmidt, S; Gregory, S; Hauser, SL; Haines, JL; Oksenberg, JR; Ritchie, MD
MLA Citation
Motsinger, AA, Brassat, D, Caillier, SJ, Erlich, HA, Walker, K, Steiner, LL, Barcellos, LF, Pericak-Vance, MA, Schmidt, S, Gregory, S, Hauser, SL, Haines, JL, Oksenberg, JR, and Ritchie, MD. "Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes." Neurogenetics 8.1 (January 2007): 11-20.
PMID
17024427
Source
pubmed
Published In
Neurogenetics
Volume
8
Issue
1
Publish Date
2007
Start Page
11
End Page
20
DOI
10.1007/s10048-006-0058-9

Identification of kalirin gene as a novel coronary artery disease gene through peak-wide association mapping on chromosome 3q13-21

Authors
Wang, L; Hauser, ER; Shah, SH; Haynes, C; Rose, JM; Harris, M; Rombaut, J; Nelson, S; Hale, AB; Crosslin, D; Gregory, SG; Granger, CB; Haines, JL; Jones, CJ; Crossman, DC; Kraus, WE; Pericak-Vance, MA; Goldschmidt-Clermont, PJ; Vance, JM
MLA Citation
Wang, L, Hauser, ER, Shah, SH, Haynes, C, Rose, JM, Harris, M, Rombaut, J, Nelson, S, Hale, AB, Crosslin, D, Gregory, SG, Granger, CB, Haines, JL, Jones, CJ, Crossman, DC, Kraus, WE, Pericak-Vance, MA, Goldschmidt-Clermont, PJ, and Vance, JM. "Identification of kalirin gene as a novel coronary artery disease gene through peak-wide association mapping on chromosome 3q13-21." October 31, 2006.
Source
wos-lite
Published In
Circulation
Volume
114
Issue
18
Publish Date
2006
Start Page
887
End Page
887

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

Authors
de Bakker, PIW; McVean, G; Sabeti, PC; Miretti, MM; Green, T; Marchini, J; Ke, X; Monsuur, AJ; Whittaker, P; Delgado, M; Morrison, J; Richardson, A; Walsh, EC; Gao, X; Galver, L; Hart, J; Hafler, DA; Pericak-Vance, M; Todd, JA; Daly, MJ; Trowsdale, J; Wijmenga, C; Vyse, TJ; Beck, S; Murray, SS; Carrington, M; Gregory, S; Deloukas, P; Rioux, JD
MLA Citation
de Bakker, PIW, McVean, G, Sabeti, PC, Miretti, MM, Green, T, Marchini, J, Ke, X, Monsuur, AJ, Whittaker, P, Delgado, M, Morrison, J, Richardson, A, Walsh, EC, Gao, X, Galver, L, Hart, J, Hafler, DA, Pericak-Vance, M, Todd, JA, Daly, MJ, Trowsdale, J, Wijmenga, C, Vyse, TJ, Beck, S, Murray, SS, Carrington, M, Gregory, S, Deloukas, P, and Rioux, JD. "A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC." Nat Genet 38.10 (October 2006): 1166-1172.
PMID
16998491
Source
pubmed
Published In
Nature Genetics
Volume
38
Issue
10
Publish Date
2006
Start Page
1166
End Page
1172
DOI
10.1038/ng1885

Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays

Authors
Gregory, SG; Johnson, NV; Connelly, JJ; Virgadamo, J; McLendon, RE; Vance, JM; Bigner, DD
MLA Citation
Gregory, SG, Johnson, NV, Connelly, JJ, Virgadamo, J, McLendon, RE, Vance, JM, and Bigner, DD. "Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
421
End Page
421

Array CGH profiling of favourable histology Wilms tumours reveals novel gains and losses associated with relapse.

Despite the excellent survival of Wilms tumour patients treated with multimodality therapy, approximately 15% will suffer from tumour relapse, where response rates are markedly reduced. We have carried out microarray-based comparative genomic hybridisation on a series of 76 Wilms tumour samples, enriched for cases which recurred, to identify changes in DNA copy number associated with clinical outcome. Using 1Mb-spaced genome-wide BAC arrays, the most significantly different genomic changes between favourable histology tumours that did (n = 37), and did not (n = 39), subsequently relapse were gains on 1q, and novel deletions at 12q24 and 18q21. Further relapse-associated loci included losses at 1q32.1, 2q36.3-2q37.1, and gain at 13q31. 1q gains correlated strongly with loss of 1p and/or 16q. In 3 of 11 cases with concurrent 1p(-)/1q(+), a breakpoint was identified at 1p13. Multiple low-level sub-megabase gains along the length of 1q were identified using chromosome 1 tiling-path arrays. One such recurrent region at 1q22-q23.1 included candidate genes RAB25, NES, CRABP2, HDGF and NTRK1, which were screened for mRNA expression using quantitative RT-PCR. These data provide a high-resolution catalogue of genomic copy number changes in relapsing favourable histology Wilms tumours.

Authors
Natrajan, R; Williams, RD; Hing, SN; Mackay, A; Reis-Filho, JS; Fenwick, K; Iravani, M; Valgeirsson, H; Grigoriadis, A; Langford, CF; Dovey, O; Gregory, SG; Weber, BL; Ashworth, A; Grundy, PE; Pritchard-Jones, K; Jones, C
MLA Citation
Natrajan, R, Williams, RD, Hing, SN, Mackay, A, Reis-Filho, JS, Fenwick, K, Iravani, M, Valgeirsson, H, Grigoriadis, A, Langford, CF, Dovey, O, Gregory, SG, Weber, BL, Ashworth, A, Grundy, PE, Pritchard-Jones, K, and Jones, C. "Array CGH profiling of favourable histology Wilms tumours reveals novel gains and losses associated with relapse." J Pathol 210.1 (September 2006): 49-58.
PMID
16823893
Source
pubmed
Published In
The Journal of Pathology
Volume
210
Issue
1
Publish Date
2006
Start Page
49
End Page
58
DOI
10.1002/path.2021

Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis.

Discrepant findings have been reported regarding an association of the apolipoprotein E (APOE) gene with the clinical course of multiple sclerosis (MS). To resolve these discrepancies, we examined common sequence variation in six candidate genes residing in a 380-kb genomic region surrounding and including the APOE locus for an association with MS severity. We genotyped at least three polymorphisms in each of six candidate genes in 1,540 Caucasian MS families (729 single-case and multiple-case families from the United States, 811 single-case families from the UK). By applying the quantitative transmission/disequilibrium test to a recently proposed MS severity score, the only statistically significant (P=0.003) association with MS severity was found for an intronic variant in the Herpes Virus Entry Mediator-B Gene PVRL2. Additional genotyping extended the association to a 16.6 kb block spanning intron 1 to intron 2 of the gene. Sequencing of PVRL2 failed to identify variants with an obvious functional role. In conclusion, the analysis of a very large data set suggests that genetic polymorphisms in PVRL2 may influence MS severity and supports the possibility that viral factors may contribute to the clinical course of MS, consistent with previous reports.

Authors
Schmidt, S; Pericak-Vance, MA; Sawcer, S; Barcellos, LF; Hart, J; Sims, J; Prokop, AM; van der Walt, J; DeLoa, C; Lincoln, RR; Oksenberg, JR; Compston, A; Hauser, SL; Haines, JL; Gregory, SG; Multiple Sclerosis Genetics Group,
MLA Citation
Schmidt, S, Pericak-Vance, MA, Sawcer, S, Barcellos, LF, Hart, J, Sims, J, Prokop, AM, van der Walt, J, DeLoa, C, Lincoln, RR, Oksenberg, JR, Compston, A, Hauser, SL, Haines, JL, Gregory, SG, and Multiple Sclerosis Genetics Group, . "Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis." Genes Immun 7.5 (July 2006): 384-392.
PMID
16738668
Source
pubmed
Published In
Genes & Immunity
Volume
7
Issue
5
Publish Date
2006
Start Page
384
End Page
392
DOI
10.1038/sj.gene.6364311

Multifactor dimensionality reduction reveals gene-gene interactions associated with multiple sclerosis susceptibility in African Americans.

Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene-gene interactions and disease susceptibility in a well-characterized African-American case-control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75-76% accuracy (P<0.01). These results demonstrate the importance of exploring both main effects and gene-gene interactions in the study of complex diseases.

Authors
Brassat, D; Motsinger, AA; Caillier, SJ; Erlich, HA; Walker, K; Steiner, LL; Cree, BAC; Barcellos, LF; Pericak-Vance, MA; Schmidt, S; Gregory, S; Hauser, SL; Haines, JL; Oksenberg, JR; Ritchie, MD
MLA Citation
Brassat, D, Motsinger, AA, Caillier, SJ, Erlich, HA, Walker, K, Steiner, LL, Cree, BAC, Barcellos, LF, Pericak-Vance, MA, Schmidt, S, Gregory, S, Hauser, SL, Haines, JL, Oksenberg, JR, and Ritchie, MD. "Multifactor dimensionality reduction reveals gene-gene interactions associated with multiple sclerosis susceptibility in African Americans." Genes Immun 7.4 (June 2006): 310-315.
PMID
16625214
Source
pubmed
Published In
Genes & Immunity
Volume
7
Issue
4
Publish Date
2006
Start Page
310
End Page
315
DOI
10.1038/sj.gene.6364299

The DNA sequence and biological annotation of human chromosome 1.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Authors
Gregory, SG; Barlow, KF; McLay, KE; Kaul, R; Swarbreck, D; Dunham, A; Scott, CE; Howe, KL; Woodfine, K; Spencer, CCA; Jones, MC; Gillson, C; Searle, S; Zhou, Y; Kokocinski, F; McDonald, L; Evans, R; Phillips, K; Atkinson, A; Cooper, R; Jones, C; Hall, RE; Andrews, TD; Lloyd, C; Ainscough, R; Almeida, JP; Ambrose, KD; Anderson, F; Andrew, RW; Ashwell, RIS; Aubin, K; Babbage, AK; Bagguley, CL; Bailey, J; Beasley, H; Bethel, G; Bird, CP; Bray-Allen, S; Brown, JY; Brown, AJ; Buckley, D; Burton, J et al.
MLA Citation
Gregory, SG, Barlow, KF, McLay, KE, Kaul, R, Swarbreck, D, Dunham, A, Scott, CE, Howe, KL, Woodfine, K, Spencer, CCA, Jones, MC, Gillson, C, Searle, S, Zhou, Y, Kokocinski, F, McDonald, L, Evans, R, Phillips, K, Atkinson, A, Cooper, R, Jones, C, Hall, RE, Andrews, TD, Lloyd, C, Ainscough, R, Almeida, JP, Ambrose, KD, Anderson, F, Andrew, RW, Ashwell, RIS, Aubin, K, Babbage, AK, Bagguley, CL, Bailey, J, Beasley, H, Bethel, G, Bird, CP, Bray-Allen, S, Brown, JY, Brown, AJ, Buckley, D, and Burton, J et al. "The DNA sequence and biological annotation of human chromosome 1." Nature 441.7091 (May 18, 2006): 315-321.
PMID
16710414
Source
pubmed
Published In
Nature
Volume
441
Issue
7091
Publish Date
2006
Start Page
315
End Page
321
DOI
10.1038/nature04727

Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH.

Pheochromocytoma is a predominantly sporadic neuroendocrine tumor derived from the adrenal medulla. Previous low resolution LOH and metaphase-CGH studies reported the loss of chromosomes 1p, 3q, 17p and 22q at various frequencies. However, the molecular mechanism(s) behind development of sporadic pheochromocytoma remains largely unknown. We have applied high-resolution tiling-path microarray-CGH with the primary aim to characterize copy number imbalances affecting chromosome 22 in 66 sporadic pheochromocytomas. We detected copy number alterations on 22q at a frequency of 44%. The predominant finding was monosomy 22 (30%), followed by terminal deletions in 8 samples (12%) and a single interstitial deletion. We further applied a chromosome 1 tiling-path array in 7 tumors with terminal deletions of 22q and found deletions of 1p in all cases. Our overall results suggest that at least 2 distinct regions on both 22q and 1p are important in the tumorigenesis of sporadic pheochromocytoma. A large proportion of pheochromocytomas also displayed indications of cellular heterogeneity. Our study is to our knowledge the first array-CGH study of sporadic pheochromocytoma. Future analysis of this tumor type should preferably be performed in the context of the entire human genome using genome-wide array-CGH, which is a superior methodological approach. Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.

Authors
Jarbo, C; Buckley, PG; Piotrowski, A; Mantripragada, KK; Benetkiewicz, M; Diaz de Ståhl, T; Langford, CF; Gregory, SG; Dralle, H; Gimm, O; Bäckdahl, M; Geli, J; Larsson, C; Westin, G; Akerström, G; Dumanski, JP
MLA Citation
Jarbo, C, Buckley, PG, Piotrowski, A, Mantripragada, KK, Benetkiewicz, M, Diaz de Ståhl, T, Langford, CF, Gregory, SG, Dralle, H, Gimm, O, Bäckdahl, M, Geli, J, Larsson, C, Westin, G, Akerström, G, and Dumanski, JP. "Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH." Int J Cancer 118.5 (March 1, 2006): 1159-1164.
PMID
16161042
Source
pubmed
Published In
International Journal of Cancer
Volume
118
Issue
5
Publish Date
2006
Start Page
1159
End Page
1164
DOI
10.1002/ijc.21385

Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease with a strong genetic component. Numerous studies have failed to consistently identify genes that confer disease susceptibility except for association with HLA-DR. Seven non-HLA regions (1q, 2q, 9q, 13q, 16q, 18p and 19q) identified in a recent genomic screen were investigated by genotyping approximately 20 single-nucleotide polymorphisms (SNPs) at approximately 1 Mb intervals. Non-parametric multipoint analyses identified a peak LOD* score of 2.99 for the 1q44 region and substantially narrowed the linkage peak to approximately 7 Mb. Ordered subset analyses (OSA) identified significant LOD score increases for 2q35 and 18p11 when ranking families by HLA-DR status and identified a significant LOD score increase in region 2q35 when ranking families by linkage to chromosome 1q44. 1q44 is particularly interesting because of linkage evidence for this region in studies of both rheumatoid arthritis and systemic lupus erythematosus.

Authors
Kenealy, SJ; Herrel, LA; Bradford, Y; Schnetz-Boutaud, N; Oksenberg, JR; Hauser, SL; Barcellos, LF; Schmidt, S; Gregory, SG; Pericak-Vance, MA; Haines, JL
MLA Citation
Kenealy, SJ, Herrel, LA, Bradford, Y, Schnetz-Boutaud, N, Oksenberg, JR, Hauser, SL, Barcellos, LF, Schmidt, S, Gregory, SG, Pericak-Vance, MA, and Haines, JL. "Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44." Genes Immun 7.1 (January 2006): 73-76.
PMID
16341055
Source
pubmed
Published In
Genes & Immunity
Volume
7
Issue
1
Publish Date
2006
Start Page
73
End Page
76
DOI
10.1038/sj.gene.6364275

GATA2 is associated with familial early-onset coronary artery disease

The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance. © 2006 Connelly et al.

Authors
Connelly, JJ; Wang, T; Cox, JE; Haynes, C; Wang, L; Shah, SH; Crosslin, DR; Hale, AB; Nelson, S; Crossman, DC; Granger, CB; Haines, JL; Jones, CJH; Vance, JM; Goldschmidt-Clermont, PJ; Kraus, WE; Hauser, ER; Gregory, SG
MLA Citation
Connelly, JJ, Wang, T, Cox, JE, Haynes, C, Wang, L, Shah, SH, Crosslin, DR, Hale, AB, Nelson, S, Crossman, DC, Granger, CB, Haines, JL, Jones, CJH, Vance, JM, Goldschmidt-Clermont, PJ, Kraus, WE, Hauser, ER, and Gregory, SG. "GATA2 is associated with familial early-onset coronary artery disease." PLoS Genetics 2.8 (2006): 1265-1273.
Source
scival
Published In
PLoS genetics
Volume
2
Issue
8
Publish Date
2006
Start Page
1265
End Page
1273
DOI
10.1371/journal.pgen.0020139

Erratum: The DNA sequence and biological annotation of human chromosome 1 (Nature (2006) 441 (315-321))

Authors
Gregory, SG; Barlow, KF; McLay, KE; Kaul, R; Swarbreck, D; Dunham, A; Scott, CE; Howe, KL; Woodfine, K; Spencer, CCA; Jones, MC; Gillson, C; Searle, S; Zhou, Y; Kokocinski, F; McDonald, L; Evans, R; Phillips, K; Atkinson, A; Cooper, R; Jones, C; Hall, RE; Andrews, TD; Lloyd, C; Ainscough, R; Almeida, JP; Ambrose, KD; Anderson, F; Andrew, RW; Ashwell, RIS; Aubin, K; Babbage, AK; Bagguley, CL; Bailey, J; Banerjee, R; Beasley, H; Bethel, G; Bird, CP; Bray-Allen, S; Brown, JY; Brown, AJ; Bryant, SP et al.
MLA Citation
Gregory, SG, Barlow, KF, McLay, KE, Kaul, R, Swarbreck, D, Dunham, A, Scott, CE, Howe, KL, Woodfine, K, Spencer, CCA, Jones, MC, Gillson, C, Searle, S, Zhou, Y, Kokocinski, F, McDonald, L, Evans, R, Phillips, K, Atkinson, A, Cooper, R, Jones, C, Hall, RE, Andrews, TD, Lloyd, C, Ainscough, R, Almeida, JP, Ambrose, KD, Anderson, F, Andrew, RW, Ashwell, RIS, Aubin, K, Babbage, AK, Bagguley, CL, Bailey, J, Banerjee, R, Beasley, H, Bethel, G, Bird, CP, Bray-Allen, S, Brown, JY, Brown, AJ, and Bryant, SP et al. "Erratum: The DNA sequence and biological annotation of human chromosome 1 (Nature (2006) 441 (315-321))." Nature 443.7114 (2006): 1013--.
Source
scival
Published In
Nature
Volume
443
Issue
7114
Publish Date
2006
Start Page
1013-
DOI
10.1038/nature05152

SNPselector: a web tool for selecting SNPs for genetic association studies.

SUMMARY: Single nucleotide polymorphisms (SNPs) are commonly used for association studies to find genes responsible for complex genetic diseases. With the recent advance of SNP technology, researchers are able to assay thousands of SNPs in a single experiment. But the process of manually choosing thousands of genotyping SNPs for tens or hundreds of genes is time consuming. We have developed a web-based program, SNPselector, to automate the process. SNPselector takes a list of gene names or a list of genomic regions as input and searches the Ensembl genes or genomic regions for available SNPs. It prioritizes these SNPs on their tagging for linkage disequilibrium, SNP allele frequencies and source, function, regulatory potential and repeat status. SNPselector outputs result in compressed Excel spreadsheet files for review by the user. AVAILABILITY: SNPselector is freely available at http://primer.duhs.duke.edu/

Authors
Xu, H; Gregory, SG; Hauser, ER; Stenger, JE; Pericak-Vance, MA; Vance, JM; Züchner, S; Hauser, MA
MLA Citation
Xu, H, Gregory, SG, Hauser, ER, Stenger, JE, Pericak-Vance, MA, Vance, JM, Züchner, S, and Hauser, MA. "SNPselector: a web tool for selecting SNPs for genetic association studies." Bioinformatics 21.22 (November 15, 2005): 4181-4186.
PMID
16179360
Source
pubmed
Published In
Bioinformatics
Volume
21
Issue
22
Publish Date
2005
Start Page
4181
End Page
4186
DOI
10.1093/bioinformatics/bti682

Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH.

BACKGROUND: Amplification of the q21-q23 region on chromosome 1 is frequently found in sarcomas and a variety of other solid tumours. Previous analyses of sarcomas have indicated the presence of at least two separate amplicons within this region, one located in 1q21 and one located near the apolipoprotein A-II (APOA2) gene in 1q23. In this study we have mapped and characterized the amplicon in 1q23 in more detail. RESULTS: We have used fluorescence in situ hybridisation (FISH) and microarray-based comparative genomic hybridisation (array CGH) to map and define the borders of the amplicon in 10 sarcomas. A subregion of approximately 800 kb was identified as the core of the amplicon. The amplification patterns of nine possible candidate target genes located to this subregion were determined by Southern blot analysis. The genes activating transcription factor 6 (ATF6) and dual specificity phosphatase 12 (DUSP12) showed the highest level of amplification, and they were also shown to be over-expressed by quantitative real-time reverse transcription PCR (RT-PCR). In general, the level of expression reflected the level of amplification in the different tumours. DUSP12 was expressed significantly higher than ATF6 in a subset of the tumours. In addition, two genes known to be transcriptionally activated by ATF6, glucose-regulated protein 78 kDa and -94 kDa (GRP78 and GRP94), were shown to be over-expressed in the tumours that showed over-expression of ATF6. CONCLUSION: ATF6 and DUSP12 seem to be the most likely candidate target genes for the 1q23 amplification in sarcomas. Both genes have possible roles in promoting cell growth, which makes them interesting candidate targets.

Authors
Kresse, SH; Berner, J-M; Meza-Zepeda, LA; Gregory, SG; Kuo, W-L; Gray, JW; Forus, A; Myklebost, O
MLA Citation
Kresse, SH, Berner, J-M, Meza-Zepeda, LA, Gregory, SG, Kuo, W-L, Gray, JW, Forus, A, and Myklebost, O. "Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH. (Published online)" Mol Cancer 4 (November 7, 2005): 39-.
PMID
16274472
Source
pubmed
Published In
Molecular Cancer
Volume
4
Publish Date
2005
Start Page
39
DOI
10.1186/1476-4598-4-39

Identification of a novel locus for left main coronary artery disease

Authors
Wang, LY; Hauser, ER; Shah, SH; Kraus, WE; Seo, D; Huang, LL; Rose, JM; Xu, H; Pedersen, B; Gregory, SG; Pericak-Vance, M; Goldschmidt-Clermont, P; Vance, JM
MLA Citation
Wang, LY, Hauser, ER, Shah, SH, Kraus, WE, Seo, D, Huang, LL, Rose, JM, Xu, H, Pedersen, B, Gregory, SG, Pericak-Vance, M, Goldschmidt-Clermont, P, and Vance, JM. "Identification of a novel locus for left main coronary artery disease." October 25, 2005.
Source
wos-lite
Published In
Circulation
Volume
112
Issue
17
Publish Date
2005
Start Page
U413
End Page
U413

Genomics and Bioinformatics

Authors
Stenger, JE; Gregory, SG
MLA Citation
Stenger, JE, and Gregory, SG. "Genomics and Bioinformatics." Genetic Analysis of Complex Diseases: Second Edition. October 7, 2005. 423-454.
Source
scopus
Publish Date
2005
Start Page
423
End Page
454
DOI
10.1002/9780471781141.ch15

A high-density screen for linkage in multiple sclerosis.

To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.

Authors
Sawcer, S; Ban, M; Maranian, M; Yeo, TW; Compston, A; Kirby, A; Daly, MJ; De Jager, PL; Walsh, E; Lander, ES; Rioux, JD; Hafler, DA; Ivinson, A; Rimmler, J; Gregory, SG; Schmidt, S; Pericak-Vance, MA; Akesson, E; Hillert, J; Datta, P; Oturai, A; Ryder, LP; Harbo, HF; Spurkland, A; Myhr, K-M; Laaksonen, M; Booth, D; Heard, R; Stewart, G; Lincoln, R; Barcellos, LF; Hauser, SL; Oksenberg, JR; Kenealy, SJ; Haines, JL; International Multiple Sclerosis Genetics Consortium,
MLA Citation
Sawcer, S, Ban, M, Maranian, M, Yeo, TW, Compston, A, Kirby, A, Daly, MJ, De Jager, PL, Walsh, E, Lander, ES, Rioux, JD, Hafler, DA, Ivinson, A, Rimmler, J, Gregory, SG, Schmidt, S, Pericak-Vance, MA, Akesson, E, Hillert, J, Datta, P, Oturai, A, Ryder, LP, Harbo, HF, Spurkland, A, Myhr, K-M, Laaksonen, M, Booth, D, Heard, R, Stewart, G, Lincoln, R, Barcellos, LF, Hauser, SL, Oksenberg, JR, Kenealy, SJ, Haines, JL, and International Multiple Sclerosis Genetics Consortium, . "A high-density screen for linkage in multiple sclerosis." Am J Hum Genet 77.3 (September 2005): 454-467.
PMID
16080120
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
77
Issue
3
Publish Date
2005
Start Page
454
End Page
467
DOI
10.1086/444547

Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma.

Substantial genomic and functional evidence from primary tumors and cell lines indicates that a consistent region of distal chromosome 1p is deleted in a sizable proportion of human neuroblastomas, suggesting that this region contains one or more tumor suppressor genes. To determine systematically and precisely the location and extent of 1p deletion in neuroblastomas, we performed allelic loss studies of 737 primary neuroblastomas and genotype analysis of 46 neuroblastoma cell lines. Together, the results defined a single region within 1p36.3 that was consistently deleted in 25% of tumors and 87% of cell lines. Two neuroblastoma patients had constitutional deletions of distal 1p36 that overlapped the tumor-defined region. The tumor- and constitutionally-derived deletions together defined a smallest region of consistent deletion (SRD) between D1S2795 and D1S253. The 1p36.3 SRD was deleted in all but one of the 184 tumors with 1p deletion. Physical mapping and DNA sequencing determined that the SRD minimally spans an estimated 729 kb. Genomic content and sequence analysis of the SRD identified 15 characterized, nine uncharacterized, and six predicted genes in the region. The RNA expression profiles of 21 of the genes were investigated in a variety of normal tissues. The SHREW1 and KCNAB2 genes both had tissue-restricted expression patterns, including expression in the nervous system. In addition, a novel gene (CHD5) with strong homology to proteins involved in chromatin remodeling was expressed mainly in neural tissues. Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region.

Authors
White, PS; Thompson, PM; Gotoh, T; Okawa, ER; Igarashi, J; Kok, M; Winter, C; Gregory, SG; Hogarty, MD; Maris, JM; Brodeur, GM
MLA Citation
White, PS, Thompson, PM, Gotoh, T, Okawa, ER, Igarashi, J, Kok, M, Winter, C, Gregory, SG, Hogarty, MD, Maris, JM, and Brodeur, GM. "Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma." Oncogene 24.16 (April 14, 2005): 2684-2694.
PMID
15829979
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
24
Issue
16
Publish Date
2005
Start Page
2684
End Page
2694
DOI
10.1038/sj.onc.1208306

Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci.

Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.

Authors
Buckley, PG; Jarbo, C; Menzel, U; Mathiesen, T; Scott, C; Gregory, SG; Langford, CF; Dumanski, JP
MLA Citation
Buckley, PG, Jarbo, C, Menzel, U, Mathiesen, T, Scott, C, Gregory, SG, Langford, CF, and Dumanski, JP. "Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci." Cancer Res 65.7 (April 1, 2005): 2653-2661.
PMID
15805262
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
7
Publish Date
2005
Start Page
2653
End Page
2661
DOI
10.1158/0008-5472.CAN-04-3651

The DNA sequence of the human X chromosome.

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Authors
Ross, MT; Grafham, DV; Coffey, AJ; Scherer, S; McLay, K; Muzny, D; Platzer, M; Howell, GR; Burrows, C; Bird, CP; Frankish, A; Lovell, FL; Howe, KL; Ashurst, JL; Fulton, RS; Sudbrak, R; Wen, G; Jones, MC; Hurles, ME; Andrews, TD; Scott, CE; Searle, S; Ramser, J; Whittaker, A; Deadman, R; Carter, NP; Hunt, SE; Chen, R; Cree, A; Gunaratne, P; Havlak, P; Hodgson, A; Metzker, ML; Richards, S; Scott, G; Steffen, D; Sodergren, E; Wheeler, DA; Worley, KC; Ainscough, R; Ambrose, KD; Ansari-Lari, MA et al.
MLA Citation
Ross, MT, Grafham, DV, Coffey, AJ, Scherer, S, McLay, K, Muzny, D, Platzer, M, Howell, GR, Burrows, C, Bird, CP, Frankish, A, Lovell, FL, Howe, KL, Ashurst, JL, Fulton, RS, Sudbrak, R, Wen, G, Jones, MC, Hurles, ME, Andrews, TD, Scott, CE, Searle, S, Ramser, J, Whittaker, A, Deadman, R, Carter, NP, Hunt, SE, Chen, R, Cree, A, Gunaratne, P, Havlak, P, Hodgson, A, Metzker, ML, Richards, S, Scott, G, Steffen, D, Sodergren, E, Wheeler, DA, Worley, KC, Ainscough, R, Ambrose, KD, and Ansari-Lari, MA et al. "The DNA sequence of the human X chromosome." Nature 434.7031 (March 17, 2005): 325-337.
PMID
15772651
Source
pubmed
Published In
Nature
Volume
434
Issue
7031
Publish Date
2005
Start Page
325
End Page
337
DOI
10.1038/nature03440

Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or "deletion with positional effect" syndrome?

Authors
Redon, R; Rio, M; Gregory, SG; Cooper, RA; Fiegler, H; Sanlaville, D; Banerjee, R; Scott, C; Carr, P; Langford, C; Cormier-Daire, V; Munnich, A; Carter, NP; Colleaux, L
MLA Citation
Redon, R, Rio, M, Gregory, SG, Cooper, RA, Fiegler, H, Sanlaville, D, Banerjee, R, Scott, C, Carr, P, Langford, C, Cormier-Daire, V, Munnich, A, Carter, NP, and Colleaux, L. "Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or "deletion with positional effect" syndrome?." J Med Genet 42.2 (February 2005): 166-171. (Letter)
PMID
15689456
Source
pubmed
Published In
Journal of medical genetics
Volume
42
Issue
2
Publish Date
2005
Start Page
166
End Page
171
DOI
10.1136/jmg.2004.023861

Natural genetic variants influencing type 1 diabetes in humans and in the NOD mouse.

The understanding of the genetic basis of type 1 diabetes and other autoimmune diseases and the application of that knowledge to their treatment, cure and eventual prevention has been a difficult goal to reach. Cumulative progress in both mouse and human are finally giving way to some successes and significant insights have been made in the last few years. Investigators have identified key immune tolerance-associated phenotypes in convincingly reliable ways that are regulated by specific diabetes-associated chromosomal intervals. The combination of positional genetics and functional studies is a powerful approach to the identification of downstream molecular events that are causal in disease aetiology. In the case of type 1 diabetes, the availability of several animal models, especially the NOD mouse, has complemented the efforts to localize human genes causing diabetes and has shown that some of the same genes and pathways are associated with autoimmunity in both species. There is also growing evidence that the initiation or progression of many autoimmune diseases is likely to be influenced by some of the same genes.

Authors
Wicker, LS; Moule, CL; Fraser, H; Penha-Goncalves, C; Rainbow, D; Garner, VES; Chamberlain, G; Hunter, K; Howlett, S; Clark, J; Gonzalez-Munoz, A; Cumiskey, AM; Tiffen, P; Howson, J; Healy, B; Smink, LJ; Kingsnorth, A; Lyons, PA; Gregory, S; Rogers, J; Todd, JA; Peterson, LB
MLA Citation
Wicker, LS, Moule, CL, Fraser, H, Penha-Goncalves, C, Rainbow, D, Garner, VES, Chamberlain, G, Hunter, K, Howlett, S, Clark, J, Gonzalez-Munoz, A, Cumiskey, AM, Tiffen, P, Howson, J, Healy, B, Smink, LJ, Kingsnorth, A, Lyons, PA, Gregory, S, Rogers, J, Todd, JA, and Peterson, LB. "Natural genetic variants influencing type 1 diabetes in humans and in the NOD mouse." Novartis Found Symp 267 (2005): 57-65.
PMID
15999801
Source
pubmed
Published In
Novartis Foundation Symposium
Volume
267
Publish Date
2005
Start Page
57
End Page
65

Strategies for genotype generation.

The identification of genomic loci linked to human disease has been greatly facilitated by the evolution of genotyping strategies and techniques. The success of these strategies continues to be based upon clear clinical assessment, accurate sample handling, and careful data management, but also increasingly upon experimental design. Technological advances in the field of genotyping are permitting increasing complex population studies to be performed. An understanding of publicly available genetic variation databases, including an awareness of the limitations of these data, and an appreciation of the strategic approaches that should be used to exploit this information will provide tremendous insight for researchers are aiming to utilize this increasingly accessible technology. As single-nucleotide polymorphisms become the mainstay of genetic analyses, it is important that their source, distribution and de novo identification before understood before they are incorporated into genetic linkage and association analyses.

Authors
Gregory, S; Gilbert, J
MLA Citation
Gregory, S, and Gilbert, J. "Strategies for genotype generation." 2005. Unit-1.3.
PMID
18428371
Source
scival
Volume
Chapter 1
Publish Date
2005
Start Page
Unit
End Page
1.3
DOI
10.1002/0471142905.hg0103s47

Organization of the MASP2 locus and its expression profile in mouse and rat.

The mouse, rat, and human MASP2 loci are situated on syntenic chromosome regions and are highly conserved. They comprise the genes for MASP-2/ MAp19, TAR DNA binding protein of 43 kDa, FRAP kinase, CDT6, Polymyositis-Scleroderma 100-kDa autoantigen, spermidine synthase, and TERE which were analyzed by annotation of available gene transcript data and cross-species comparison of available genomic sequences. The human and rat genes for spermidine synthase have an additional intron compared to the mouse gene. The mouse and rat genes for Polymyositis-Scleroderma 100-kDa autoantigen have an additional exon compared to the human gene. We find support for the hypothesis that the MAp19-specific exon within the MASP2 gene may have originated in a transposable element. Blocks of highly conserved intronic sequences were found in the MASP2 gene and the TARDBP gene. The expression of all genes within the MASP2 locus was analyzed in mouse and rat. The restricted expression of MASP-2 and MAp19 mRNA in liver contrasts with the ubiquitous expression of all neighboring genes studied.

Authors
Stover, CM; Lynch, NJ; Hanson, SJ; Windbichler, M; Gregory, SG; Schwaeble, WJ
MLA Citation
Stover, CM, Lynch, NJ, Hanson, SJ, Windbichler, M, Gregory, SG, and Schwaeble, WJ. "Organization of the MASP2 locus and its expression profile in mouse and rat." Mamm Genome 15.11 (November 2004): 887-900.
PMID
15672593
Source
pubmed
Published In
Mammalian Genome
Volume
15
Issue
11
Publish Date
2004
Start Page
887
End Page
900

Organization and evolution of a gene-rich region of the mouse genome: a 12.7-Mb region deleted in the Del(13)Svea36H mouse.

Del(13)Svea36H (Del36H) is a deletion of approximately 20% of mouse chromosome 13 showing conserved synteny with human chromosome 6p22.1-6p22.3/6p25. The human region is lost in some deletion syndromes and is the site of several disease loci. Heterozygous Del36H mice show numerous phenotypes and may model aspects of human genetic disease. We describe 12.7 Mb of finished, annotated sequence from Del36H. Del36H has a higher gene density than the draft mouse genome, reflecting high local densities of three gene families (vomeronasal receptors, serpins, and prolactins) which are greatly expanded relative to human. Transposable elements are concentrated near these gene families. We therefore suggest that their neighborhoods are gene factories, regions of frequent recombination in which gene duplication is more frequent. The gene families show different proportions of pseudogenes, likely reflecting different strengths of purifying selection and/or gene conversion. They are also associated with relatively low simple sequence concentrations, which vary across the region with a periodicity of approximately 5 Mb. Del36H contains numerous evolutionarily conserved regions (ECRs). Many lie in noncoding regions, are detectable in species as distant as Ciona intestinalis, and therefore are candidate regulatory sequences. This analysis will facilitate functional genomic analysis of Del36H and provides insights into mouse genome evolution.

Authors
Mallon, A-M; Wilming, L; Weekes, J; Gilbert, JGR; Ashurst, J; Peyrefitte, S; Matthews, L; Cadman, M; McKeone, R; Sellick, CA; Arkell, R; Botcherby, MRM; Strivens, MA; Campbell, RD; Gregory, S; Denny, P; Hancock, JM; Rogers, J; Brown, SDM
MLA Citation
Mallon, A-M, Wilming, L, Weekes, J, Gilbert, JGR, Ashurst, J, Peyrefitte, S, Matthews, L, Cadman, M, McKeone, R, Sellick, CA, Arkell, R, Botcherby, MRM, Strivens, MA, Campbell, RD, Gregory, S, Denny, P, Hancock, JM, Rogers, J, and Brown, SDM. "Organization and evolution of a gene-rich region of the mouse genome: a 12.7-Mb region deleted in the Del(13)Svea36H mouse." Genome Res 14.10A (October 2004): 1888-1901.
PMID
15364904
Source
pubmed
Published In
Genome research
Volume
14
Issue
10A
Publish Date
2004
Start Page
1888
End Page
1901
DOI
10.1101/gr.2478604

Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Authors
Sawcer, SJ; Maranian, M; Singlehurst, S; Yeo, T; Compston, A; Daly, MJ; De Jager, PL; Gabriel, S; Hafler, DA; Ivinson, AJ; Lander, ES; Rioux, JD; Walsh, E; Gregory, SG; Schmidt, S; Pericak-Vance, MA; Barcellos, L; Hauser, SL; Oksenberg, JR; Kenealy, SJ; Haines, JL
MLA Citation
Sawcer, SJ, Maranian, M, Singlehurst, S, Yeo, T, Compston, A, Daly, MJ, De Jager, PL, Gabriel, S, Hafler, DA, Ivinson, AJ, Lander, ES, Rioux, JD, Walsh, E, Gregory, SG, Schmidt, S, Pericak-Vance, MA, Barcellos, L, Hauser, SL, Oksenberg, JR, Kenealy, SJ, and Haines, JL. "Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping." Hum Mol Genet 13.17 (September 1, 2004): 1943-1949.
PMID
15238506
Source
pubmed
Published In
Human Molecular Genetics
Volume
13
Issue
17
Publish Date
2004
Start Page
1943
End Page
1949
DOI
10.1093/hmg/ddh202

Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.

At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.2. In this study, using a series of novel NOD.B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28. Genomic sequence comparison of the two functional candidate genes, Ctla4 and Icos, from the B6 (resistant at Idd5.1) and the NOD (susceptible at Idd5.1) strains revealed 62 single nucleotide polymorphisms (SNPs), only two of which were in coding regions. One of these coding SNPs, base 77 of Ctla4 exon 2, is a synonymous SNP and has been correlated previously with type 1 diabetes susceptibility and differential expression of a CTLA-4 isoform. Additional expression studies in this work support the hypothesis that this SNP in exon 2 is the genetic variation causing the biological effects of Idd5.1. Analysis of additional congenic strains has also localized Idd5.2 to a small region (1.52 Mb) of chromosome 1, but in contrast to the Idd5.1 interval, Idd5.2 contains at least 45 genes. Notably, the Idd5.2 region still includes the functionally polymorphic Nramp1 gene. Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs.

Authors
Wicker, LS; Chamberlain, G; Hunter, K; Rainbow, D; Howlett, S; Tiffen, P; Clark, J; Gonzalez-Munoz, A; Cumiskey, AM; Rosa, RL; Howson, JM; Smink, LJ; Kingsnorth, A; Lyons, PA; Gregory, S; Rogers, J; Todd, JA; Peterson, LB
MLA Citation
Wicker, LS, Chamberlain, G, Hunter, K, Rainbow, D, Howlett, S, Tiffen, P, Clark, J, Gonzalez-Munoz, A, Cumiskey, AM, Rosa, RL, Howson, JM, Smink, LJ, Kingsnorth, A, Lyons, PA, Gregory, S, Rogers, J, Todd, JA, and Peterson, LB. "Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse." J Immunol 173.1 (July 1, 2004): 164-173.
PMID
15210771
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
173
Issue
1
Publish Date
2004
Start Page
164
End Page
173

Comprehensive analysis of candidate modifier genes for multiple sclerosis (MS) on chromosome 19q13

Authors
Haines, JL; Schmidt, S; Sawcer, S; Barcellos, LF; Gregory, SG; Sims, J; Booze, M; Vance, JM; Oksenberg, JR; Hauser, SL; Compston, A; Pericak-Vance, MA
MLA Citation
Haines, JL, Schmidt, S, Sawcer, S, Barcellos, LF, Gregory, SG, Sims, J, Booze, M, Vance, JM, Oksenberg, JR, Hauser, SL, Compston, A, and Pericak-Vance, MA. "Comprehensive analysis of candidate modifier genes for multiple sclerosis (MS) on chromosome 19q13." November 2003.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
73
Issue
5
Publish Date
2003
Start Page
368
End Page
368

Identification of a structurally distinct CD101 molecule encoded in the 950-kb Idd10 region of NOD mice.

Genes affecting autoimmune type 1 diabetes susceptibility in the nonobese diabetic (NOD) mouse (Idd loci) have been mapped using a congenic strain breeding strategy. In the present study, we used a combination of BAC clone contig construction, polymorphism analysis of DNA from congenic strains, and sequence mining of the human orthologous region to generate an integrated map of the Idd10 region on mouse chromosome 3. We found seven genes and one pseudogene in the 950-kb Idd10 region. Although all seven genes in the interval are Idd10 candidates, we suggest the gene encoding the EWI immunoglobulin subfamily member EWI-101 (Cd101) as the most likely Idd10 candidate because of the previously reported immune-associated properties of the human CD101 molecule. Additional support for the candidacy of Cd101 is the presence of 17 exonic single-nucleotide polymorphisms that differ between the NOD and B6 sequences, 10 causing amino acid substitutions in the predicted CD101 protein. Four of these 10 substitutions are nonconservative, 2 of which could potentially alter N-linked glycosylation. Considering our results together with those previous reports that antibodies recognizing human CD101 modulate human T-cell and dendritic cell function, there is now justification to test whether the alteration of CD101 function affects autoimmune islet destruction.

Authors
Penha-Gonçalves, C; Moule, C; Smink, LJ; Howson, J; Gregory, S; Rogers, J; Lyons, PA; Suttie, JJ; Lord, CJ; Peterson, LB; Todd, JA; Wicker, LS
MLA Citation
Penha-Gonçalves, C, Moule, C, Smink, LJ, Howson, J, Gregory, S, Rogers, J, Lyons, PA, Suttie, JJ, Lord, CJ, Peterson, LB, Todd, JA, and Wicker, LS. "Identification of a structurally distinct CD101 molecule encoded in the 950-kb Idd10 region of NOD mice." Diabetes 52.6 (June 2003): 1551-1556.
PMID
12765969
Source
pubmed
Published In
Diabetes
Volume
52
Issue
6
Publish Date
2003
Start Page
1551
End Page
1556

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Authors
Ueda, H; Howson, JMM; Esposito, L; Heward, J; Snook, H; Chamberlain, G; Rainbow, DB; Hunter, KMD; Smith, AN; Di Genova, G; Herr, MH; Dahlman, I; Payne, F; Smyth, D; Lowe, C; Twells, RCJ; Howlett, S; Healy, B; Nutland, S; Rance, HE; Everett, V; Smink, LJ; Lam, AC; Cordell, HJ; Walker, NM; Bordin, C; Hulme, J; Motzo, C; Cucca, F; Hess, JF; Metzker, ML; Rogers, J; Gregory, S; Allahabadia, A; Nithiyananthan, R; Tuomilehto-Wolf, E; Tuomilehto, J; Bingley, P; Gillespie, KM; Undlien, DE; Rønningen, KS et al.
MLA Citation
Ueda, H, Howson, JMM, Esposito, L, Heward, J, Snook, H, Chamberlain, G, Rainbow, DB, Hunter, KMD, Smith, AN, Di Genova, G, Herr, MH, Dahlman, I, Payne, F, Smyth, D, Lowe, C, Twells, RCJ, Howlett, S, Healy, B, Nutland, S, Rance, HE, Everett, V, Smink, LJ, Lam, AC, Cordell, HJ, Walker, NM, Bordin, C, Hulme, J, Motzo, C, Cucca, F, Hess, JF, Metzker, ML, Rogers, J, Gregory, S, Allahabadia, A, Nithiyananthan, R, Tuomilehto-Wolf, E, Tuomilehto, J, Bingley, P, Gillespie, KM, Undlien, DE, and Rønningen, KS et al. "Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease." Nature 423.6939 (May 29, 2003): 506-511.
PMID
12724780
Source
pubmed
Published In
Nature
Volume
423
Issue
6939
Publish Date
2003
Start Page
506
End Page
511
DOI
10.1038/nature01621

Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P.

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant inflammatory disease with a high degree of penetrance that is characterized by episodes of rash, arthralgia, fever, conjunctivitis, and leukocytosis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44, and subsequently the gene ( CIAS1) responsible for FCAS was identified. In this paper, we describe the physical and genetic mapping of the FCAS locus, and we report a large ancestral haplotype and a new disease-causing mutation. A BAC contig of approximately 3 Mb was developed and subsequently used for high throughput sequencing. We identified a critical region of 4 cM using rare crossover events in four large North American FCAS families. An unusually large shared haplotype (40 cM) was identified in three of the four families. We found a single heterozygous missense mutation (T1058C=L353P) in exon 3 of CIAS1 in all four families that is responsible for the large majority of FCAS cases described in the literature. We also report a comprehensive list of intragenic single nucleotide polymorphisms. The data provided here will assist others researching the 1q44 region and will aid clinicians in the diagnosis of FCAS.

Authors
Hoffman, HM; Gregory, SG; Mueller, JL; Tresierras, M; Broide, DH; Wanderer, AA; Kolodner, RD
MLA Citation
Hoffman, HM, Gregory, SG, Mueller, JL, Tresierras, M, Broide, DH, Wanderer, AA, and Kolodner, RD. "Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P." Hum Genet 112.2 (February 2003): 209-216.
PMID
12522564
Source
pubmed
Published In
Human Genetics
Volume
112
Issue
2
Publish Date
2003
Start Page
209
End Page
216
DOI
10.1007/s00439-002-0860-x

Initial sequencing and comparative analysis of the mouse genome.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Authors
Mouse Genome Sequencing Consortium, ; Waterston, RH; Lindblad-Toh, K; Birney, E; Rogers, J; Abril, JF; Agarwal, P; Agarwala, R; Ainscough, R; Alexandersson, M; An, P; Antonarakis, SE; Attwood, J; Baertsch, R; Bailey, J; Barlow, K; Beck, S; Berry, E; Birren, B; Bloom, T; Bork, P; Botcherby, M; Bray, N; Brent, MR; Brown, DG; Brown, SD; Bult, C; Burton, J; Butler, J; Campbell, RD; Carninci, P; Cawley, S; Chiaromonte, F; Chinwalla, AT; Church, DM; Clamp, M; Clee, C; Collins, FS; Cook, LL et al.
MLA Citation
Mouse Genome Sequencing Consortium, , Waterston, RH, Lindblad-Toh, K, Birney, E, Rogers, J, Abril, JF, Agarwal, P, Agarwala, R, Ainscough, R, Alexandersson, M, An, P, Antonarakis, SE, Attwood, J, Baertsch, R, Bailey, J, Barlow, K, Beck, S, Berry, E, Birren, B, Bloom, T, Bork, P, Botcherby, M, Bray, N, Brent, MR, Brown, DG, Brown, SD, Bult, C, Burton, J, Butler, J, Campbell, RD, Carninci, P, Cawley, S, Chiaromonte, F, Chinwalla, AT, Church, DM, Clamp, M, Clee, C, Collins, FS, and Cook, LL et al. "Initial sequencing and comparative analysis of the mouse genome." Nature 420.6915 (December 5, 2002): 520-562.
PMID
12466850
Source
pubmed
Published In
Nature
Volume
420
Issue
6915
Publish Date
2002
Start Page
520
End Page
562
DOI
10.1038/nature01262

Linkage and association with type 1 diabetes on chromosome 1q42.

Type 1 diabetes is a complex disorder with multiple genetic loci and environmental factors contributing to disease etiology. In the current study, a human type 1 diabetes candidate region on chromosome 1q42 was mapped at high marker density in a panel of 616 multiplex type 1 diabetic families. To facilitate the identification and evaluation of candidate genes, a physical map of the 7-cM region surrounding the maximum logarithm of odds (LOD) score (2.46, P = 0.0004) was constructed. Genes were identified in the 500-kb region surrounding the marker yielding the peak LOD score and evaluated for polymorphism by resequencing. Single-nucleotide polymorphisms (SNPs) identified in these genes as well as other anonymous markers were tested for allelic association with type 1 diabetes by both family-based and case-control methods. A haplotype formed by common alleles at three adjacent markers (D1S225, D1S2383, and D1S251) was preferentially transmitted to affected offspring in type 1 diabetic families (nominal P = 0.006). These findings extend the evidence supporting the existence of a type 1 diabetes susceptibility locus on chromosome 1q42 and identify a candidate region amenable to positional cloning efforts.

Authors
Ewens, KG; Johnson, LN; Wapelhorst, B; O'Brien, K; Gutin, S; Morrison, VA; Street, C; Gregory, SG; Spielman, RS; Concannon, P
MLA Citation
Ewens, KG, Johnson, LN, Wapelhorst, B, O'Brien, K, Gutin, S, Morrison, VA, Street, C, Gregory, SG, Spielman, RS, and Concannon, P. "Linkage and association with type 1 diabetes on chromosome 1q42." Diabetes 51.11 (November 2002): 3318-3325.
PMID
12401725
Source
pubmed
Published In
Diabetes
Volume
51
Issue
11
Publish Date
2002
Start Page
3318
End Page
3325

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Authors
Parvari, R; Hershkovitz, E; Grossman, N; Gorodischer, R; Loeys, B; Zecic, A; Mortier, G; Gregory, S; Sharony, R; Kambouris, M; Sakati, N; Meyer, BF; Al Aqeel, AI; Al Humaidan, AK; Al Zanhrani, F; Al Swaid, A; Al Othman, J; Diaz, GA; Weiner, R; Khan, KTS; Gordon, R; Gelb, BD; HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium,
MLA Citation
Parvari, R, Hershkovitz, E, Grossman, N, Gorodischer, R, Loeys, B, Zecic, A, Mortier, G, Gregory, S, Sharony, R, Kambouris, M, Sakati, N, Meyer, BF, Al Aqeel, AI, Al Humaidan, AK, Al Zanhrani, F, Al Swaid, A, Al Othman, J, Diaz, GA, Weiner, R, Khan, KTS, Gordon, R, Gelb, BD, and HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium, . "Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome." Nat Genet 32.3 (November 2002): 448-452.
PMID
12389028
Source
pubmed
Published In
Nature Genetics
Volume
32
Issue
3
Publish Date
2002
Start Page
448
End Page
452
DOI
10.1038/ng1012

A physical map of the mouse genome.

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.

Authors
Gregory, SG; Sekhon, M; Schein, J; Zhao, S; Osoegawa, K; Scott, CE; Evans, RS; Burridge, PW; Cox, TV; Fox, CA; Hutton, RD; Mullenger, IR; Phillips, KJ; Smith, J; Stalker, J; Threadgold, GJ; Birney, E; Wylie, K; Chinwalla, A; Wallis, J; Hillier, L; Carter, J; Gaige, T; Jaeger, S; Kremitzki, C; Layman, D; Maas, J; McGrane, R; Mead, K; Walker, R; Jones, S; Smith, M; Asano, J; Bosdet, I; Chan, S; Chittaranjan, S; Chiu, R; Fjell, C; Fuhrmann, D; Girn, N; Gray, C; Guin, R; Hsiao, L; Krzywinski, M et al.
MLA Citation
Gregory, SG, Sekhon, M, Schein, J, Zhao, S, Osoegawa, K, Scott, CE, Evans, RS, Burridge, PW, Cox, TV, Fox, CA, Hutton, RD, Mullenger, IR, Phillips, KJ, Smith, J, Stalker, J, Threadgold, GJ, Birney, E, Wylie, K, Chinwalla, A, Wallis, J, Hillier, L, Carter, J, Gaige, T, Jaeger, S, Kremitzki, C, Layman, D, Maas, J, McGrane, R, Mead, K, Walker, R, Jones, S, Smith, M, Asano, J, Bosdet, I, Chan, S, Chittaranjan, S, Chiu, R, Fjell, C, Fuhrmann, D, Girn, N, Gray, C, Guin, R, Hsiao, L, and Krzywinski, M et al. "A physical map of the mouse genome." Nature 418.6899 (August 15, 2002): 743-750.
PMID
12181558
Source
pubmed
Published In
Nature
Volume
418
Issue
6899
Publish Date
2002
Start Page
743
End Page
750
DOI
10.1038/nature00957

A candidate gene for congenital bilateral isolated ptosis identified by molecular analysis of a de novo balanced translocation.

Ptosis is defined as drooping of the upper eyelid and can impair full visual acuity. It occurs in a number of forms including congenital bilateral isolated ptosis, which may be familial and for which two linkage groups are known on chromosomes 1p32-34.1 and Xq24-27.1. We describe the analysis of the chromosome breakpoints in a patient with congenital bilateral isolated ptosis and a de novo balanced translocation 46,XY,t(1;8)(p34.3;q21.12). Both breakpoints were localized by fluorescence in situ hybridisation with yeast artificial chromosomes, bacterial artificial chromosomes and P1 artificial chromosomes. The derived chromosomes were isolated by flow-sorting, amplified by degenerate oligonucleotide-primed polymerase chain reaction and analyzed by sequence tagged sites amplification to map the breakpoints at a resolution that enabled molecular characterization by DNA sequencing. The 1p breakpoint lies ~13 Mb distal to the previously reported linkage locus at 1p32-1p34.1 and does not disrupt a coding sequence, whereas the chromosome 8 breakpoint disrupts a gene homologous to the mouse zfh-4gene. Murine zfh-4 codes for a zinc finger homeodomain protein and is a transcription factor expressed in both muscle and nerve tissue. Human ZFH-4 is therefore a candidate gene for congenital bilateral isolated ptosis.

Authors
McMullan, TW; Crolla, JA; Gregory, SG; Carter, NP; Cooper, RA; Howell, GR; Robinson, DO
MLA Citation
McMullan, TW, Crolla, JA, Gregory, SG, Carter, NP, Cooper, RA, Howell, GR, and Robinson, DO. "A candidate gene for congenital bilateral isolated ptosis identified by molecular analysis of a de novo balanced translocation." Hum Genet 110.3 (March 2002): 244-250.
PMID
11935336
Source
pubmed
Published In
Human Genetics
Volume
110
Issue
3
Publish Date
2002
Start Page
244
End Page
250
DOI
10.1007/s00439-002-0679-5

Matroshka and ectopic polymorphisms: Two new classes of DNA sequence variation identified at the Van der Woude syndrome locus on 1q32-q41.

Van der Woude syndrome (VWS) is an orofacial clefting disorder with an autosomal dominant pattern of inheritance. In our efforts to clone the VWS gene, 900 kb of genomic sequence from the VWS candidate region at chromosome 1q32-q41 was analyzed for new DNA sequence variants. We observed that in clone CTA-321i20 a 7922 bp sequence is absent relative to the sequence present in PAC clone RP4-782d21 at positions 1669-9590, suggesting the presence of a deletion/insertion (del/ins) polymorphism. Embedded in this 7922 bp region was a TTCC short tandem repeat (STR). Genotype analysis showed that both the internal STR and the (del/ins) mutation were true polymorphisms. This is a novel example of intraallelic variation, a polymorphism within a polymorphism, and we suggest that it be termed a "Matroshka" polymorphism. Further genetic and DNA sequence analysis indicated that the ancestral state of the 1669-9590 del/ins polymorphism was the insertion allele and that the original deletion mutation probably occurred only once. A second class of novel DNA sequence variation was discovered on chromosome 5 that shared a 328 bp identical sequence with this region on chromosome 1. A single nucleotide polymorphism (SNP) was detected by SSCP using a pair of primers derived from the chromosome 1 sequence. Surprisingly, these primers also amplified the identical locus on chromosome 5, and the SNP was only located on chromosome 5. Since the probe unexpectedly detected alleles from another locus, we suggest that this type of sequence variant be termed an "ectopic" polymorphism. These two novel classes of DNA sequence polymorphisms have the potential to confound genetic and DNA sequence analysis and may also contribute to variation in disease phenotypes.

Authors
Watanabe, Y; Murray, JC; Bjork, BC; Bird, CP; Chiang, PW; Gregory, SG; Kurnit, DM; Schutte, BC
MLA Citation
Watanabe, Y, Murray, JC, Bjork, BC, Bird, CP, Chiang, PW, Gregory, SG, Kurnit, DM, and Schutte, BC. "Matroshka and ectopic polymorphisms: Two new classes of DNA sequence variation identified at the Van der Woude syndrome locus on 1q32-q41." Hum Mutat 18.5 (November 2001): 422-434.
PMID
11668635
Source
pubmed
Published In
Human Mutation
Volume
18
Issue
5
Publish Date
2001
Start Page
422
End Page
434
DOI
10.1002/humu.1213

An SSLP marker-anchored BAC framework map of the mouse genome.

We have constructed a BAC framework map of the mouse genome consisting of 2,808 PCR-confirmed BAC clusters, using a previously described method. Fingerprints of BACs from selected clusters confirm the accuracy of the map. Combined with BAC fingerprint data, the framework map covers 37% of the mouse genome.

Authors
Cai, WW; Chow, CW; Damani, S; Gregory, SG; Marra, M; Bradley, A
MLA Citation
Cai, WW, Chow, CW, Damani, S, Gregory, SG, Marra, M, and Bradley, A. "An SSLP marker-anchored BAC framework map of the mouse genome." Nat Genet 29.2 (October 2001): 133-134.
PMID
11586294
Source
pubmed
Published In
Nature Genetics
Volume
29
Issue
2
Publish Date
2001
Start Page
133
End Page
134
DOI
10.1038/ng1001-133

The human gene for mannan-binding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p36.2-3.

The proteases of the lectin pathway of complement activation, MASP-1 and MASP-2, are encoded by two separate genes. The MASP1 gene is located on chromosome 3q27, the MASP2 gene on chromosome 1p36.23-31. The genes for the classical complement activation pathway proteases, C1r and C1s, are linked on chromosome 12p13. We have shown that the MASP2 gene encodes two gene products, the 76 kDa MASP-2 serine protease and a plasma protein of 19 kDa, termed MAp19 or sMAP. Both gene products are components of the lectin pathway activation complex. We present the complete primary structure of the human MASP2 gene and the tight cluster that this locus forms with non-complement genes. A comparison of the MASP2 gene with the previously characterised C1s gene revealed identical positions of introns separating orthologous coding sequences, underlining the hypothesis that the C1s and MASP2 genes arose by exon shuffling from one ancestral gene.

Authors
Stover, C; Endo, Y; Takahashi, M; Lynch, NJ; Constantinescu, C; Vorup-Jensen, T; Thiel, S; Friedl, H; Hankeln, T; Hall, R; Gregory, S; Fujita, T; Schwaeble, W
MLA Citation
Stover, C, Endo, Y, Takahashi, M, Lynch, NJ, Constantinescu, C, Vorup-Jensen, T, Thiel, S, Friedl, H, Hankeln, T, Hall, R, Gregory, S, Fujita, T, and Schwaeble, W. "The human gene for mannan-binding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p36.2-3." Genes Immun 2.3 (May 2001): 119-127.
PMID
11426320
Source
pubmed
Published In
Genes & Immunity
Volume
2
Issue
3
Publish Date
2001
Start Page
119
End Page
127
DOI
10.1038/sj.gene.6363745

Comparative physical and transcript maps of approximately 1 Mb around loop-tail, a gene for severe neural tube defects on distal mouse chromosome 1 and human chromosome 1q22-q23.

The homozygous loop-tail (Lp) mouse has a severe neural tube closure defect, analogous to the craniorachischisis phenotype seen in humans. Linkage analysis and physical mapping have previously localized the Lp locus to a region on mouse chromosome 1 defined by the markers D1Mit113-Tagln2. Here we report the construction of sequence-ready bacterial clone contigs encompassing the Lp critical region in both mouse and the orthologous human region (1q22-q23). Twenty-two genes, one EST, and one pseudogene have been identified using a combination of EST database screening, exon amplification, and genomic sequence analysis. The preliminary gene map is Cen-Estm33-AA693056-Ly9-Cd48-Slam-Cd84-Kiaa1215-Nhlh1-Kiaa0253-Copa-Pxf-H326-Pea15-Casq1-Atp1a4-Atp1a2-Estm34-Kcnj9-Kcnj10-Kiaa1355-Tagln2-Nesg1-Crp-Tel. The genes between Slam and Kiaa1355 are positional candidates for Lp. The comparative gene content and order are identical between mouse and human, indicating a high degree of conservation between the two species in this region. Together, the physical and transcript maps described here serve as resources for the identification of the Lp mutation and further define the conservation of this genomic region between mouse and human.

Authors
Doudney, K; Murdoch, JN; Paternotte, C; Bentley, L; Gregory, S; Copp, AJ; Stanier, P
MLA Citation
Doudney, K, Murdoch, JN, Paternotte, C, Bentley, L, Gregory, S, Copp, AJ, and Stanier, P. "Comparative physical and transcript maps of approximately 1 Mb around loop-tail, a gene for severe neural tube defects on distal mouse chromosome 1 and human chromosome 1q22-q23." Genomics 72.2 (March 1, 2001): 180-192.
PMID
11401431
Source
pubmed
Published In
Genomics
Volume
72
Issue
2
Publish Date
2001
Start Page
180
End Page
192
DOI
10.1006/geno.2000.6463

A physical map of the human genome.

The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.

Authors
McPherson, JD; Marra, M; Hillier, L; Waterston, RH; Chinwalla, A; Wallis, J; Sekhon, M; Wylie, K; Mardis, ER; Wilson, RK; Fulton, R; Kucaba, TA; Wagner-McPherson, C; Barbazuk, WB; Gregory, SG; Humphray, SJ; French, L; Evans, RS; Bethel, G; Whittaker, A; Holden, JL; McCann, OT; Dunham, A; Soderlund, C; Scott, CE; Bentley, DR; Schuler, G; Chen, HC; Jang, W; Green, ED; Idol, JR; Maduro, VV; Montgomery, KT; Lee, E; Miller, A; Emerling, S; Kucherlapati, ; Gibbs, R; Scherer, S; Gorrell, JH et al.
MLA Citation
McPherson, JD, Marra, M, Hillier, L, Waterston, RH, Chinwalla, A, Wallis, J, Sekhon, M, Wylie, K, Mardis, ER, Wilson, RK, Fulton, R, Kucaba, TA, Wagner-McPherson, C, Barbazuk, WB, Gregory, SG, Humphray, SJ, French, L, Evans, RS, Bethel, G, Whittaker, A, Holden, JL, McCann, OT, Dunham, A, Soderlund, C, Scott, CE, Bentley, DR, Schuler, G, Chen, HC, Jang, W, Green, ED, Idol, JR, Maduro, VV, Montgomery, KT, Lee, E, Miller, A, Emerling, S, Kucherlapati, , Gibbs, R, Scherer, S, and Gorrell, JH et al. "A physical map of the human genome." Nature 409.6822 (February 15, 2001): 934-941.
PMID
11237014
Source
pubmed
Published In
Nature
Volume
409
Issue
6822
Publish Date
2001
Start Page
934
End Page
941
DOI
10.1038/35057157

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X.

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.

Authors
Bentley, DR; Deloukas, P; Dunham, A; French, L; Gregory, SG; Humphray, SJ; Mungall, AJ; Ross, MT; Carter, NP; Dunham, I; Scott, CE; Ashcroft, KJ; Atkinson, AL; Aubin, K; Beare, DM; Bethel, G; Brady, N; Brook, JC; Burford, DC; Burrill, WD; Burrows, C; Butler, AP; Carder, C; Catanese, JJ; Clee, CM; Clegg, SM; Cobley, V; Coffey, AJ; Cole, CG; Collins, JE; Conquer, JS; Cooper, RA; Culley, KM; Dawson, E; Dearden, FL; Durbin, RM; de Jong, PJ; Dhami, PD; Earthrowl, ME; Edwards, CA; Evans, RS et al.
MLA Citation
Bentley, DR, Deloukas, P, Dunham, A, French, L, Gregory, SG, Humphray, SJ, Mungall, AJ, Ross, MT, Carter, NP, Dunham, I, Scott, CE, Ashcroft, KJ, Atkinson, AL, Aubin, K, Beare, DM, Bethel, G, Brady, N, Brook, JC, Burford, DC, Burrill, WD, Burrows, C, Butler, AP, Carder, C, Catanese, JJ, Clee, CM, Clegg, SM, Cobley, V, Coffey, AJ, Cole, CG, Collins, JE, Conquer, JS, Cooper, RA, Culley, KM, Dawson, E, Dearden, FL, Durbin, RM, de Jong, PJ, Dhami, PD, Earthrowl, ME, Edwards, CA, and Evans, RS et al. "The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X." Nature 409.6822 (February 15, 2001): 942-943.
PMID
11237015
Source
pubmed
Published In
Nature
Volume
409
Issue
6822
Publish Date
2001
Start Page
942
End Page
943
DOI
10.1038/35057165

Initial sequencing and analysis of the human genome.

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Authors
Lander, ES; Linton, LM; Birren, B; Nusbaum, C; Zody, MC; Baldwin, J; Devon, K; Dewar, K; Doyle, M; FitzHugh, W; Funke, R; Gage, D; Harris, K; Heaford, A; Howland, J; Kann, L; Lehoczky, J; LeVine, R; McEwan, P; McKernan, K; Meldrim, J; Mesirov, JP; Miranda, C; Morris, W; Naylor, J; Raymond, C; Rosetti, M; Santos, R; Sheridan, A; Sougnez, C; Stange-Thomann, Y; Stojanovic, N; Subramanian, A; Wyman, D; Rogers, J; Sulston, J; Ainscough, R; Beck, S; Bentley, D; Burton, J; Clee, C; Carter, N et al.
MLA Citation
Lander, ES, Linton, LM, Birren, B, Nusbaum, C, Zody, MC, Baldwin, J, Devon, K, Dewar, K, Doyle, M, FitzHugh, W, Funke, R, Gage, D, Harris, K, Heaford, A, Howland, J, Kann, L, Lehoczky, J, LeVine, R, McEwan, P, McKernan, K, Meldrim, J, Mesirov, JP, Miranda, C, Morris, W, Naylor, J, Raymond, C, Rosetti, M, Santos, R, Sheridan, A, Sougnez, C, Stange-Thomann, Y, Stojanovic, N, Subramanian, A, Wyman, D, Rogers, J, Sulston, J, Ainscough, R, Beck, S, Bentley, D, Burton, J, Clee, C, and Carter, N et al. "Initial sequencing and analysis of the human genome." Nature 409.6822 (February 15, 2001): 860-921.
PMID
11237011
Source
pubmed
Published In
Nature
Volume
409
Issue
6822
Publish Date
2001
Start Page
860
End Page
921
DOI
10.1038/35057062

Comprehensive analysis of chromosome 1p deletions in neuroblastoma.

BACKGROUND: Chromosome 1p deletions are common in advanced neuroblastomas, but the biological and clinical implications of this clonal rearrangement remain controversial. Previous studies of chromosome 1p loss of heterozygosity (LOH) have been limited by analyses of relatively small number of tumors derived from heterogeneously assessed and treated patient populations. Therefore, a strictly representative cohort of 288 Children's Cancer Group neuroblastoma patients treated on the most recent phase III therapeutic trials was identified. PROCEDURE: Primary tumors from these patients were analyzed for LOH at precisely mapped and highly informative 1p polymorphic loci located from 1p32 to 1p36.3 by multiplex PCR. RESULTS: Ninety-three primary tumor specimens (32%) had LOH at multiple 1p36 marker loci. All 1p deletions overlapped the previously determined smallest region of overlap (SRO). One tumor had a small terminal deletion completely within 1p36.3, allowing for further refinement of the 1p36 SRO. We found no evidence to support an additional, nonoverlapping region of LOH within 1p32-36. We confirmed the strong correlation of 1p36 LOH with MYCN amplification (P < 0.001), advanced disease stage (P < 0.001), and decreased both 3-year event-free survival and overall survival probabilities (P< 0.001). When stratified for MYCN amplification status or entered into a multivariate analysis, 1p36 LOH remained predictive for decreased event-free survival, but not overall survival probability. CONCLUSIONS: These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse.

Authors
Maris, JM; Guo, C; Blake, D; White, PS; Hogarty, MD; Thompson, PM; Rajalingam, V; Gerbing, R; Stram, DO; Matthay, KK; Seeger, RC; Brodeur, GM
MLA Citation
Maris, JM, Guo, C, Blake, D, White, PS, Hogarty, MD, Thompson, PM, Rajalingam, V, Gerbing, R, Stram, DO, Matthay, KK, Seeger, RC, and Brodeur, GM. "Comprehensive analysis of chromosome 1p deletions in neuroblastoma." January 2001.
PMID
11464900
Source
epmc
Published In
Pediatric Blood and Cancer
Volume
36
Issue
1
Publish Date
2001
Start Page
32
End Page
36
DOI
10.1002/1096-911x(20010101)36:1<32::aid-mpo1009>3.0.co;2-0

Detailed molecular analysis of 1p36 in neuroblastoma.

BACKGROUND: Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor. PROCEDURE: We analyzed the status of 1p36 in primary neuroblastomas and cell lines to define the region of consistent rearrangement. RESULTS: Loss of heterozygosity (LOH) studies of primary neuro blastomas identified allelic loss in 135 of 503 tumors (27%), with the smallest region of overlap (SRO) defined distal to D15214 (1p36.3). No homozygous deletions were detected at 120 loci mapping to 1p36.1-p36.3 in a panel of 46 neuroblastoma cell lines. A recently identified patient with neuroblastoma was found to have a constitutional deletion within 1p36.2-p36.3, and this deletion, when combined with the LOH results, defined a smaller SRO of one megabase within 1p36.3. We constructed a comprehensive integrated map of chromosome 1 containing 11,000 markers and large-insert clones, a high-resolution radiation hybrid (RH) map of 1p36, and a P1-artificial chromosome (PAC) contig spanning the SRO, to further characterize the region of interest. Over 768 kb (75%) of the SRO has been sequenced to completion. Further analysis of distal 1p identified 113 transcripts localizing to 1p36, 21 of which were mapped within the SRO. CONCLUSION: This analysis will identify suitable positional candidate transcripts for mutational screening and subsequent identification of the 1p36.3 neuroblastoma suppressor gene.

Authors
White, PS; Thompson, PM; Seifried, BA; Sulman, EP; Jensen, SJ; Guo, C; Maris, JM; Hogarty, MD; Allen, C; Biegel, JA; Matise, TC; Gregory, SG; Reynolds, CP; Brodeur, GM
MLA Citation
White, PS, Thompson, PM, Seifried, BA, Sulman, EP, Jensen, SJ, Guo, C, Maris, JM, Hogarty, MD, Allen, C, Biegel, JA, Matise, TC, Gregory, SG, Reynolds, CP, and Brodeur, GM. "Detailed molecular analysis of 1p36 in neuroblastoma." Med Pediatr Oncol 36.1 (January 2001): 37-41.
PMID
11464901
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
36
Issue
1
Publish Date
2001
Start Page
37
End Page
41
DOI
10.1002/1096-911X(20010101)36:1<37::AID-MPO1010>3.0.CO;2-L

Report and abstracts of the sixth international workshop on human chromosome 1 mapping 2000. Iowa City, Iowa, USA. 30 September-3 October 2000.

Authors
Schutte, BC; Carpten, JD; Forus, A; Gregory, SG; Horii, A; White, PS
MLA Citation
Schutte, BC, Carpten, JD, Forus, A, Gregory, SG, Horii, A, and White, PS. Report and abstracts of the sixth international workshop on human chromosome 1 mapping 2000. Iowa City, Iowa, USA. 30 September-3 October 2000. 2001.
PMID
11306795
Source
pubmed
Published In
Cytogenetics and cell genetics
Publish Date
2001
Start Page
23
End Page
41
DOI
10.1159/000056867

Comprehensive analysis of chromosome 1p deletions in neuroblastoma

Background. Chromosome 1p deletions are common in advanced neuroblastomas, but the biological and clinical implications of this clonal rearrangement remain controversial. Previous studies of chromosome 1p loss of heterozygosity (LOH) have been limited by analyses of relatively small number of tumors derived from heterogeneously assessed and treated patient populations. Therefore, a strictly representative cohort of 288 Children's Cancer Group neuroblastoma patients treated on the most recent phase III therapeutic trials was identified. Procedure. Primary tumors from these patients were analyzed for LOH at precisely mapped and highly informative 1p polymorphic loci located from 1p32 to 1p36.3 by multiplex PCR. Results. Ninety-three primary tumor specimens (32%) had LOH at multiple 1p36 marker loci. All 1p deletions overlapped the previously determined smallest region of overlap (SRO). One tumor had a small terminal deletion completely within 1p36.3, allowing for further refinement of the 1p36 SRO. We found no evidence to support an additional, nonoverlapping region of LOH within 1p32-36. We confirmed the strong correlation of 1p36 LOH with MYCN amplification (P < 0.001), advanced disease stage (P < 0.001), and decreased both 3-year event-free survival and overall survival probabilities (P < 0.001). When stratified for MYCN amplification status or entered into a multivariate analysis, 1p36 LOH remained predictive for decreased event-free survival, but not overall survival probability. Conclusions. These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse. © 2001 Wiley-Liss, Inc.

Authors
White, PS; Thompson, PM; Seifried, BA; Sulman, EP; Jensen, SJ; Guo, C; Maris, JM; Hogarty, MD; Allen, C; Biegel, JA; Matise, TC; Gregory, SG; Reynolds, CP; Brodeur, GM
MLA Citation
White, PS, Thompson, PM, Seifried, BA, Sulman, EP, Jensen, SJ, Guo, C, Maris, JM, Hogarty, MD, Allen, C, Biegel, JA, Matise, TC, Gregory, SG, Reynolds, CP, and Brodeur, GM. "Comprehensive analysis of chromosome 1p deletions in neuroblastoma." Medical and Pediatric Oncology 36.1 (2001): 32-36.
Source
scival
Published In
Pediatric Blood and Cancer
Volume
36
Issue
1
Publish Date
2001
Start Page
32
End Page
36
DOI
10.1002/1096-911X(20010101)36:1<32::AID-MPO1009>3.0.CO;2-0

A 6-Mb high-resolution physical and transcription map encompassing the hereditary prostate cancer 1 (HPC1) region.

Several hereditary disease loci have been genetically mapped to the chromosome 1q24-q31 interval, including the hereditary prostate cancer 1 (HPC1) locus. Here, we report the construction of a 20-Mb yeast artificial chromosome contig and a high-resolution 6-Mb sequence-ready bacterial artificial chromosome (BAC)/P1-derived artificial chromosome (PAC) contig of 1q25 by sequence and computational analysis, STS content mapping, and chromosome walking. One hundred thirty-six new STSs, including 10 novel simple sequence repeat polymorphisms that are being used for genetic refinement of multiple disease loci, have been generated from this contig and are shown to map to the 1q25 interval. The integrity of the 6-Mb BAC/PAC contig has been confirmed by restriction fingerprinting, and this contig is being used as a template for human chromosome 1 genome sequencing. A transcription mapping effort has resulted in the precise localization of 18 known genes and 31 ESTs by database searching, exon trapping, direct cDNA hybridization, and sample sequencing of BACs from the 1q25 contig. An additional 11 known genes and ESTs have been placed within the larger 1q24-q31 interval. These transcription units represent candidate genes for multiple hereditary diseases, including HPC1.

Authors
Carpten, JD; Makalowska, I; Robbins, CM; Scott, N; Sood, R; Connors, TD; Bonner, TI; Smith, JR; Faruque, MU; Stephan, DA; Pinkett, H; Morgenbesser, SD; Su, K; Graham, C; Gregory, SG; Williams, H; McDonald, L; Baxevanis, AD; Klingler, KW; Landes, GM; Trent, JM
MLA Citation
Carpten, JD, Makalowska, I, Robbins, CM, Scott, N, Sood, R, Connors, TD, Bonner, TI, Smith, JR, Faruque, MU, Stephan, DA, Pinkett, H, Morgenbesser, SD, Su, K, Graham, C, Gregory, SG, Williams, H, McDonald, L, Baxevanis, AD, Klingler, KW, Landes, GM, and Trent, JM. "A 6-Mb high-resolution physical and transcription map encompassing the hereditary prostate cancer 1 (HPC1) region." Genomics 64.1 (February 15, 2000): 1-14.
PMID
10708513
Source
pubmed
Published In
Genomics
Volume
64
Issue
1
Publish Date
2000
Start Page
1
End Page
14
DOI
10.1006/geno.1999.6051

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Authors
Shackleton, S; Lloyd, DJ; Jackson, SN; Evans, R; Niermeijer, MF; Singh, BM; Schmidt, H; Brabant, G; Kumar, S; Durrington, PN; Gregory, S; O'Rahilly, S; Trembath, RC
MLA Citation
Shackleton, S, Lloyd, DJ, Jackson, SN, Evans, R, Niermeijer, MF, Singh, BM, Schmidt, H, Brabant, G, Kumar, S, Durrington, PN, Gregory, S, O'Rahilly, S, and Trembath, RC. "LMNA, encoding lamin A/C, is mutated in partial lipodystrophy." Nat Genet 24.2 (February 2000): 153-156.
PMID
10655060
Source
pubmed
Published In
Nature Genetics
Volume
24
Issue
2
Publish Date
2000
Start Page
153
End Page
156
DOI
10.1038/72807

A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41.

Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and palate and accounts for approximately 2% of all cleft lip and palate cases. Distinguishing characteristics include cleft lip with or without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal-dominant mode of transmission with a high degree of penetrance. Previously, the VWS locus was mapped to a 1.6-cM region in 1q32-q41 between D1S491 and D1S205, and a 4.4-Mb contig of YAC clones of this region was constructed. In the current investigation, gene-based and anonymous STSs were developed from the existing physical map and were then used to construct a contig of sequence-ready bacterial clones across the entire VWS critical region. All STSs and BAC clones were shared with the Sanger Centre, which developed a contig of PAC clones over the same region. A subset of 11 clones from both contigs was selected for high-throughput sequence analysis across the approximately 1.1-Mb region; all but two of these clones have been sequenced completely. Over 900 kb of genomic sequence, including the 350-kb VWS critical region, were analyzed and revealed novel polymorphisms, including an 8-kb deletion/insertion, and revealed 4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes. The positional candidates LAMB3, G0S2, HIRF6, and HSD11 were excluded as the VWS gene by mutation analysis. A preliminary gene map for the VWS critical region is as follows: [see text] 41-TEL. The data provided here will help lead to the identification of the VWS gene, and this study provides a model for how laboratories that have a regional interest in the human genome can contribute to the sequencing efforts of the entire human genome.

Authors
Schutte, BC; Bjork, BC; Coppage, KB; Malik, MI; Gregory, SG; Scott, DJ; Brentzell, LM; Watanabe, Y; Dixon, MJ; Murray, JC
MLA Citation
Schutte, BC, Bjork, BC, Coppage, KB, Malik, MI, Gregory, SG, Scott, DJ, Brentzell, LM, Watanabe, Y, Dixon, MJ, and Murray, JC. "A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41." Genome Res 10.1 (January 2000): 81-94.
PMID
10645953
Source
pubmed
Published In
Genome research
Volume
10
Issue
1
Publish Date
2000
Start Page
81
End Page
94

Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness.

Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.

Authors
Labay, V; Raz, T; Baron, D; Mandel, H; Williams, H; Barrett, T; Szargel, R; McDonald, L; Shalata, A; Nosaka, K; Gregory, S; Cohen, N
MLA Citation
Labay, V, Raz, T, Baron, D, Mandel, H, Williams, H, Barrett, T, Szargel, R, McDonald, L, Shalata, A, Nosaka, K, Gregory, S, and Cohen, N. "Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness." Nat Genet 22.3 (July 1999): 300-304.
PMID
10391221
Source
pubmed
Published In
Nature Genetics
Volume
22
Issue
3
Publish Date
1999
Start Page
300
End Page
304
DOI
10.1038/10372

Report of the fifth international workshop on human chromosome 1 mapping 1999.

Authors
White, PS; Forus, A; Matise, TC; Schutte, BC; Spieker, N; Stanier, P; Vance, JM; Gregory, SG
MLA Citation
White, PS, Forus, A, Matise, TC, Schutte, BC, Spieker, N, Stanier, P, Vance, JM, and Gregory, SG. Report of the fifth international workshop on human chromosome 1 mapping 1999. 1999.
PMID
10702659
Source
pubmed
Published In
Cytogenetics and cell genetics
Publish Date
1999
Start Page
143
End Page
171
DOI
10.1159/000015458

Fifth International Workshop on Human Chromosome 1 Mapping 1999, the Sanger Centre, Cambridge, UK, August 5-7 1999: Report

Authors
White, PS; Forus, A; Matise, TC; Schutte, BC; Spieker, N; Stanier, P; Vance, JM; Gregory, SG
MLA Citation
White, PS, Forus, A, Matise, TC, Schutte, BC, Spieker, N, Stanier, P, Vance, JM, and Gregory, SG. "Fifth International Workshop on Human Chromosome 1 Mapping 1999, the Sanger Centre, Cambridge, UK, August 5-7 1999: Report." Cytogenetics and Cell Genetics 87.3-4 (1999): 143-163.
Source
scival
Published In
Cytogenetics and cell genetics
Volume
87
Issue
3-4
Publish Date
1999
Start Page
143
End Page
163

Report of the fourth international workshop on human chromosome 1 mapping 1998

Authors
Gregory, SG; Vaudin, M; Wooster, R; Coleman, M; Mischke, D; Porter, C; Schutte, BC; White, P; Vance, JM
MLA Citation
Gregory, SG, Vaudin, M, Wooster, R, Coleman, M, Mischke, D, Porter, C, Schutte, BC, White, P, and Vance, JM. Report of the fourth international workshop on human chromosome 1 mapping 1998. 1998.
PMID
10072573
Source
pubmed
Published In
Cytogenetics and cell genetics
Publish Date
1998
Start Page
147
End Page
175
DOI
10.1159/000015174

Fourth International Workshop on Human Chromosome 1 Mapping 1998, Sanger Centre, Cambridge, United Kingdom, June 25-27 1998: Report

Authors
Gregory, SG; Vaudin, M; Wooster, R; Coleman, M; Mischke, D; Porter, C; Schutte, BC; White, P; Vance, JM
MLA Citation
Gregory, SG, Vaudin, M, Wooster, R, Coleman, M, Mischke, D, Porter, C, Schutte, BC, White, P, and Vance, JM. "Fourth International Workshop on Human Chromosome 1 Mapping 1998, Sanger Centre, Cambridge, United Kingdom, June 25-27 1998: Report." Cytogenetics and Cell Genetics 83.3-4 (1998): 147-167.
Source
scival
Published In
Cytogenetics and Cell Genetics
Volume
83
Issue
3-4
Publish Date
1998
Start Page
147
End Page
167

Genome mapping by fluorescent fingerprinting.

The construction of sequence-ready maps of overlapping genomic clones is central to large-scale genome sequencing. We have implemented a method for fluorescent fingerprinting of bacterial clones to assemble contig maps. The method utilizes three spectrally distinct fluorescently tagged dideoxy ATPs to specifically label the HindIII termini in HindIII and Sau3AI restriction digests of clones that are multiplexed prior to electrophoresis and data collection. There is excellent reproducibility of raw data, improved resolution of large fragments, and concordance between the results obtained using this and the equivalent radioactive protocol. This method also allows detection of smaller overlaps between clones when compared to the analysis of restriction digests on nondenaturing agarose gels.

Authors
Gregory, SG; Howell, GR; Bentley, DR
MLA Citation
Gregory, SG, Howell, GR, and Bentley, DR. "Genome mapping by fluorescent fingerprinting." Genome Res 7.12 (December 1997): 1162-1168.
PMID
9414321
Source
pubmed
Published In
Genome research
Volume
7
Issue
12
Publish Date
1997
Start Page
1162
End Page
1168

Report and abstracts of the third international workshop on human chromosome 1 mapping 1997.

Authors
Vance, JM; Matise, TC; Wooster, R; Schutte, BC; Bruns, GA; van Roy, N; Brodeur, GM; Tao, YX; Gregory, S; Weith, A; Vaudin, M; White, P
MLA Citation
Vance, JM, Matise, TC, Wooster, R, Schutte, BC, Bruns, GA, van Roy, N, Brodeur, GM, Tao, YX, Gregory, S, Weith, A, Vaudin, M, and White, P. Report and abstracts of the third international workshop on human chromosome 1 mapping 1997. 1997.
PMID
9465885
Source
pubmed
Published In
Cytogenetics and cell genetics
Publish Date
1997
Start Page
154
End Page
182

Third International Chromosome 1 Maping Workshop, Duke University, Durham, NC, USA, 25-27 April 1997: Report of the third international workshop on human chromosome 1 mapping 1997

Authors
Vance, JM; Matise, TC; Wooster, R; Schutte, BC; Bruns, GAP; Roy, NV; Brodeur, GM; Tao, YX; Gregory, S; Weith, A; Vaudin, M; White, P
MLA Citation
Vance, JM, Matise, TC, Wooster, R, Schutte, BC, Bruns, GAP, Roy, NV, Brodeur, GM, Tao, YX, Gregory, S, Weith, A, Vaudin, M, and White, P. Third International Chromosome 1 Maping Workshop, Duke University, Durham, NC, USA, 25-27 April 1997: Report of the third international workshop on human chromosome 1 mapping 1997. 1997.
Source
scival
Publish Date
1997
Start Page
154
End Page
179

An integrated YAC map of the human X chromosome.

The human X chromosome is associated with a large number of disease phenotypes, principally because of its unique mode of inheritance that tends to reveal all recessive disorders in males. With the longer term goal of identifying and characterizing most of these genes, we have adopted a chromosome-wide strategy to establish a YAC contig map. We have performed > 3250 inter Alu-PCR product hybridizations to identify overlaps between YAC clones. Positional information associated with many of these YAC clones has been derived from our Reference Library Database and a variety of other public sources. We have constructed a YAC contig map of the X chromosome covering 125 Mb of DNA in 25 contigs and containing 906 YAC clones. These contigs have been verified extensively by FISH and by gel and hybridization fingerprinting techniques. This independently derived map exceeds the coverage of recently reported X chromosome maps built as part of whole-genome YAC maps.

Authors
Roest Crollius, H; Ross, MT; Grigoriev, A; Knights, CJ; Holloway, E; Misfud, J; Li, K; Playford, M; Gregory, SG; Humphray, SJ; Coffey, AJ; See, CG; Marsh, S; Vatcheva, R; Kumlien, J; Labella, T; Lam, V; Rak, KH; Todd, K; Mott, R; Graeser, D; Rappold, G; Zehetner, G; Poustka, A; Bentley, DR; Monaco, AP; Lehrach, H
MLA Citation
Roest Crollius, H, Ross, MT, Grigoriev, A, Knights, CJ, Holloway, E, Misfud, J, Li, K, Playford, M, Gregory, SG, Humphray, SJ, Coffey, AJ, See, CG, Marsh, S, Vatcheva, R, Kumlien, J, Labella, T, Lam, V, Rak, KH, Todd, K, Mott, R, Graeser, D, Rappold, G, Zehetner, G, Poustka, A, Bentley, DR, Monaco, AP, and Lehrach, H. "An integrated YAC map of the human X chromosome." Genome Res 6.10 (October 1996): 943-955.
PMID
8908513
Source
pubmed
Published In
Genome research
Volume
6
Issue
10
Publish Date
1996
Start Page
943
End Page
955

Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus (CPX) including the proximal X-Y homology breakpoint within Xq21.3.

The gene for X-linked cleft palate (CPX) has previously been mapped in an Icelandic kindred between the unordered proximal markers DXS1002/DXS349/DXS95 and the distal marker DXYS1X, which maps to the proximal end of the X-Y homology region in Xq21.3. Using six sequence-tagged sites (STSs) within the region, a total of 91 yeast artificial chromosome (YAC) clones were isolated and overlapped in a single contig that spans approximately 3.1 Mb between DXS1002 and DXYS1X. The order of microsatellite and STS markers in this was established as DXS1002-DXS1168-DSX349-DXS95-DXS364-DXS 1196-DXS262-DXS110-DXS1066-(DXS1169, DXS1222)-DXS472-DXS1217-DXYS1X. A long-range restriction map of this region was created using eight nonchimeric, overlapping YAC clones. Analysis of newly positioned polymorphic markers in recombinant individuals from the Icelandic family has enabled us to identify DXS1196 and DXS1217 as the flanking markers for CPX. The maximum physical distance containing the CPX gene has been estimated to be 2.0 Mb, which is spanned by a minimum set of five nonchimeric YAC clones. In addition, YAC end clone and STS analyses have pinpointed the location of the proximal boundary of the X-Y homology region within the map.

Authors
Forbes, SA; Brennan, L; Richardson, M; Coffey, A; Cole, CG; Gregory, SG; Bentley, DR; Mumm, S; Moore, GE; Stanier, P
MLA Citation
Forbes, SA, Brennan, L, Richardson, M, Coffey, A, Cole, CG, Gregory, SG, Bentley, DR, Mumm, S, Moore, GE, and Stanier, P. "Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus (CPX) including the proximal X-Y homology breakpoint within Xq21.3." Genomics 31.1 (January 1, 1996): 36-43.
PMID
8808277
Source
pubmed
Published In
Genomics
Volume
31
Issue
1
Publish Date
1996
Start Page
36
End Page
43
DOI
10.1006/geno.1996.0006

An Xp22.1-p22.2 YAC contig encompassing the disease loci for RS, KFSD, CLS, HYP and RP15: refined localization of RS.

To facilitate the positional cloning of the genes involved in retinoschisis (RS), keratosis follicularis spinulosa decalvans (KFSD), Coffin-Lowry syndrome (CLS), X-linked hypophosphatemic rickets (XLH, locus name HYP) and X-linked dominant cone-rod degeneration (locus name RP15), we have extended the molecular map of the Xp22 region. Screening of several YAC libraries allowed us to identify 156 YACs, 52 of which localize between markers DXS414 (P90) and DXS451 (kQST80H1). Analysis of their marker content facilitated the construction of a YAC contig from the region spanning (in this order): DXS414 - DXS987 - DXS207 - DXS1053 - DXS197 - DXS 43 - DXS1195 - DXS418 - DXS999 - PDHA1 - DXS7161 - DXS443 - DXS 7592 - DXS1229 - DXS365 - DXS7101 - DXS7593 - DXS1052 - DXS274 - DXS989 - DXS451. The region between DXS414 and DXS451 covers about 4.5-5 Mb. Two additional markers (DXS7593 and DXS7592) were placed in the region, thereby increasing the genetic resolution. Using the deduced marker order, the analysis of key recombinants in families segregating RS allowed us to refine the critical region for RS to 0.6 Mb, between DXS418 and DXS7161.

Authors
Van de Vosse, E; Bergen, AA; Meershoek, EJ; Oosterwijk, JC; Gregory, S; Bakker, B; Weissenbach, J; Coffey, AJ; van Ommen, GJ; Den Dunnen, JT
MLA Citation
Van de Vosse, E, Bergen, AA, Meershoek, EJ, Oosterwijk, JC, Gregory, S, Bakker, B, Weissenbach, J, Coffey, AJ, van Ommen, GJ, and Den Dunnen, JT. "An Xp22.1-p22.2 YAC contig encompassing the disease loci for RS, KFSD, CLS, HYP and RP15: refined localization of RS." Eur J Hum Genet 4.2 (1996): 101-104.
PMID
8744027
Source
pubmed
Published In
European Journal of Human Genetics
Volume
4
Issue
2
Publish Date
1996
Start Page
101
End Page
104

Alu-PCR fingerprinting of YACs.

Authors
Coffey, A; Gregory, S; Cole, CG
MLA Citation
Coffey, A, Gregory, S, and Cole, CG. "Alu-PCR fingerprinting of YACs." 1996. 97-114.
PMID
8597809
Source
pubmed
Volume
54
Publish Date
1996
Start Page
97
End Page
114

Addendum: Identification of the breast cancer susceptibility gene BRCA2 (Nature (1995) 378 (789-792))

Authors
Wooster, R; Bignell, G; Lancaster, J; Swift, S; Seal, S; Mangion, J; Collins, N; Gregory, S; Gumbs, C; Michlem, G; Barfoot, R; Hamoudi, R; Patel, S; Rice, C; Biggs, P; Hashim, Y; Smith, A; Connor, F; Arason, A
MLA Citation
Wooster, R, Bignell, G, Lancaster, J, Swift, S, Seal, S, Mangion, J, Collins, N, Gregory, S, Gumbs, C, Michlem, G, Barfoot, R, Hamoudi, R, Patel, S, Rice, C, Biggs, P, Hashim, Y, Smith, A, Connor, F, and Arason, A. "Addendum: Identification of the breast cancer susceptibility gene BRCA2 (Nature (1995) 378 (789-792))." Nature 379.6567 (1996): 749--.
Source
scival
Published In
Nature
Volume
379
Issue
6567
Publish Date
1996
Start Page
749-

Identification of the breast cancer susceptibility gene BRCA2.

In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

Authors
Wooster, R; Bignell, G; Lancaster, J; Swift, S; Seal, S; Mangion, J; Collins, N; Gregory, S; Gumbs, C; Micklem, G
MLA Citation
Wooster, R, Bignell, G, Lancaster, J, Swift, S, Seal, S, Mangion, J, Collins, N, Gregory, S, Gumbs, C, and Micklem, G. "Identification of the breast cancer susceptibility gene BRCA2." Nature 378.6559 (December 21, 1995): 789-792.
PMID
8524414
Source
pubmed
Published In
Nature
Volume
378
Issue
6559
Publish Date
1995
Start Page
789
End Page
792
DOI
10.1038/378789a0

A high-resolution integrated physical, cytogenetic, and genetic map of human chromosome 11: distal p13 to proximal p15.1

We describe a detailed physical map of human chromosome 11, extending from the distal part of p13 through the entirety of p14 to proximal p15.1. The primary level of mapping is based on chromosome breakpoints that divide the region into 20 intervals. At higher resolution YACs cover approximately 12 Mb of the region, and in many places overlapping cosmids are ordered in contiguous arrays. The map incorporates 18 known genes, including precise localization of the GTF2H1 gene encoding the 62-kDa subunit of TFIIH. We have also localized four expressed sequences of unknown function. The physical map incorporates genetic markers that allow relationships between physical and genetic distance to be examined, and similarly includes markers from a radiation hybrid map of 11. The cytogenetic location of cosmids has been examined on high-resolution banded chromosomes by fluorescence in situ hybridization, and FLpter values have been determined. The map therefore fully integrates physical, genic, genetic, and cytogenetic information and should provide a robust framework for the rapid and accurate assignment of new markers at a high level of resolution in this region of 11p. © 1995.

Authors
Fantes, JA; Oghene, K; Boyle, S; Danes, S; Fletcher, JM; Bruford, EA; Williamson, K; Seawright, A; Schedl, A; Hanson, I; Zehetner, G; Bhogal, R; Lehrach, H; Gregory, S; Williams, J; Little, PFR; Sellar, GC; Hoovers, J; Mannens, M; Weissenbach, J; Junien, C; Heyningen, VV; Bickmore, WA
MLA Citation
Fantes, JA, Oghene, K, Boyle, S, Danes, S, Fletcher, JM, Bruford, EA, Williamson, K, Seawright, A, Schedl, A, Hanson, I, Zehetner, G, Bhogal, R, Lehrach, H, Gregory, S, Williams, J, Little, PFR, Sellar, GC, Hoovers, J, Mannens, M, Weissenbach, J, Junien, C, Heyningen, VV, and Bickmore, WA. "A high-resolution integrated physical, cytogenetic, and genetic map of human chromosome 11: distal p13 to proximal p15.1." Genomics 25.2 (1995): 447-461.
PMID
7789978
Source
scival
Published In
Genomics
Volume
25
Issue
2
Publish Date
1995
Start Page
447
End Page
461

An integrated physical map of 210 markers assigned to the short arm of human chromosome 11.

Using a panel of patient cell lines with chromosomal breakpoints, we constructed a physical map for the short arm of human chromosome 11. We focused on 11p15, a chromosome band harboring at least 25 known genes and associated with the Beckwith-Wiedemann syndrome, several childhood tumors, and genomic imprinting. This underlines the need for a physical map for this region. We divided the short arm of chromosome 11 into 18 breakpoint regions, and a large series of new and previously described genes and markers was mapped within these intervals using fluorescence in situ hybridization. Cosmid fingerprint analysis showed that 19 of these markers were included in cosmid contigs. A detailed 10-Mb pulsed-field physical map of the region 11p15.3-pter was constructed. These three different approaches enabled the high-resolution mapping of 210 markers, including 22 known genes.

Authors
Redeker, E; Hoovers, JM; Alders, M; van Moorsel, CJ; Ivens, AC; Gregory, S; Kalikin, L; Bliek, J; de Galan, L; van den Bogaard, R
MLA Citation
Redeker, E, Hoovers, JM, Alders, M, van Moorsel, CJ, Ivens, AC, Gregory, S, Kalikin, L, Bliek, J, de Galan, L, and van den Bogaard, R. "An integrated physical map of 210 markers assigned to the short arm of human chromosome 11." Genomics 21.3 (June 1994): 538-550.
PMID
7959730
Source
pubmed
Published In
Genomics
Volume
21
Issue
3
Publish Date
1994
Start Page
538
End Page
550

The generation of ordered sets of cosmid DNA clones from human chromosome region 11p.

We describe progress in a continuing project aimed at the generation of an overlapping cosmid DNA clone map of the short arm of human chromosome 11. The automated procedures used to prepare DNA samples and the computerized data collection and recording systems are described. We also demonstrate the use of the clones as reagents for the rapid isolation of genomic DNAs containing smaller probed regions. We have isolated approximately 4700 human cosmid DNA clones from mouse/human hybrid cell lines that contain predominantly human chromosomal region 11p. Of the DNA in the cell lines, 60% is derived from this chromosomal region, and the remaining 40% is derived from regions of chromosomes 3, 19, and 20. A total of 4159 clones have been fingerprinted to identify potential overlaps, and we have developed 535 sets ("contigs"). Using random modeling, it is estimated that 65% of 11p must be contained in the analyzed cosmids. The database of clones has been used to identify single or overlapping clones from noncosmid DNA probes. Examples are presented. It is proposed that cosmid reference filters be distributed to requesting laboratories.

Authors
Heding, IJ; Ivens, AC; Wilson, J; Strivens, M; Gregory, S; Hoovers, JM; Mannens, M; Redeker, B; Porteous, D; van Heyningen, V
MLA Citation
Heding, IJ, Ivens, AC, Wilson, J, Strivens, M, Gregory, S, Hoovers, JM, Mannens, M, Redeker, B, Porteous, D, and van Heyningen, V. "The generation of ordered sets of cosmid DNA clones from human chromosome region 11p." Genomics 13.1 (May 1992): 89-94.
PMID
1577496
Source
pubmed
Published In
Genomics
Volume
13
Issue
1
Publish Date
1992
Start Page
89
End Page
94

Epigenetic Analysis of Adipose Stem Cells in Obesity Identifies Dysregulation of Critical Pathways in Musculoskeletal Regeneration and Disease.

Authors
Little, D; Wu, CL; D'Amico, R; Corcoran, D; Gregory, S; Guilak, F
MLA Citation
Little, D, Wu, CL, D'Amico, R, Corcoran, D, Gregory, S, and Guilak, F. "Epigenetic Analysis of Adipose Stem Cells in Obesity Identifies Dysregulation of Critical Pathways in Musculoskeletal Regeneration and Disease." Orthopedic Research Society. 2015. Las Vegas, NV.
Source
manual
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