Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

Wang, Benjamin, D'Agostino, Govindaraju, Heard-Costa, Hwang Shih-Jen, Murabito, Newton-Cheh Christopher, O'Donnell, Seshadri Sudha, Vasan, Wolf, Levy Daniel, Larson, Atwood, Cupples, Fox, Guo Chao-Yu

Description

Cardiovascular disease (CVD) and its most common manifestations – including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) – are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes. Methods In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001. Results Six associations yielded p < 10 -5 . The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 × 10 -6 ; major CHD, rs2549513, p = 9.7 × 10 -6 ; AF, rs958546, p = 4.8 × 10 -6 ; HF: rs740363, p = 8.8 × 10 -6 . Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 – 1.9 × 10 -5 ) and major CHD (p 2.5 – 3.5 × 10 -4 ) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 × 10 -6 ) and HF (p = 1.2 × 10 -4 ). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 . .

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• Publié par: biomed
• Publié le: 01 janvier 2007
• Nombre de lectures: 73
• Langue: English

Extrait

BMC Medical Genetics

BioMedCentral

Open Access Research Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes 1,2 1,31,3,4 Martin G Larson*, Larry D Atwood, Emelia J Benjamin, 1,5 1,21 L Adrienne Cupples, Ralph B D'Agostino Sr, Caroline S Fox, 1,3 1,31,3 Diddahally R Govindaraju, ChaoYu Guo, Nancy L HeardCosta, Shih 1 1,61,7,8 Jen Hwang, Joanne M Murabito, Christopher NewtonCheh, 1,7 1,31,3,4 Christopher J O'Donnell, Sudha Seshadri, Ramachandran S Vasan, 1,7 1,31 Thomas J Wang, Philip A Wolfand Daniel Levy

1 2 Address: TheNational Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA,Department of Mathematics and 3 4 Statistics, Boston University, Boston, MA, USA,Boston University School of Medicine, Boston, MA, USA,Whitaker Cardiovascular Institute, 5 Boston University School of Medicine, Boston, MA, USA,Department of Biostatistics, Boston University School of Public Health, Boston, MA, 6 7 USA, Sectionof General Internal Medicine, Boston University School of Medicine, Boston, MA, USA,Cardiology Division, Massachusetts General 8 Hospital, Harvard Medical School, Boston, MA, USA andBroad Institute of Harvard and MIT, Cambridge, MA, USA

Email: Martin G Larson*  [e-mail]; Larry D Atwood  [e-mail]; Emelia J Benjamin  [e-mail]; L Adrienne Cupples  [e-mail]; Ralph B D'Agostino  [e-mail]; Caroline S Fox  [e-mail]; Diddahally R Govindaraju  [e-mail]; ChaoYu Guo  Chao[e-mail]; Nancy L HeardCosta  [e-mail]; ShihJen Hwang  [e-mail]; Joanne M Murabito  [e-mail]; Christopher NewtonCheh  [e-mail]; Christopher J O'Donnell  [e-mail]; Sudha Seshadri  [e-mail]; Ramachandran S Vasan  [e-mail]; Thomas J Wang  [e-mail]; Philip A Wolf  [e-mail]; Daniel Levy  [e-mail] * Corresponding author

Published: 19 September 2007 <SsuVpasplaenm</e<>eltitditohT>p<>retonste>R><ne/h<iamrFcranamghSrteaHe>otur<htl>tp/:w/wwb.oiemcdgluyd1000,00snientraucl.ceor>cloruu/sp/e<<l<p/p>untelmteimytl>ohprosmms/icsoenrtetnp/fd1/74-t1i3d2e05p-8-S1-info.pdf</Rmaadndnarcaahn,hehC-nootsirhCOJerphllneon'DMeigs,JamesBehreNtwhCirtspoJEuiaqasCllheLle,yve,hsinaD,DaFoxneSroliei,btoltJGinlelime>Eorited<e>aC,nimajneBJa BMC Medical Genetics2007,8doi:10.1186/1471-2350-8-S1-S5(Suppl 1):S5 This article is available from: http://www.biomedcentral.com/1471-2350/8/S1/S5 © 2007 Larson et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:Cardiovascular disease (CVD) and its most common manifestations – including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) – are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes. Methods:In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency≥0.10, genotype call rate≥0.80, and Hardy-Weinberg equilibrium p-value≥0.001. -5 Results:. The lowest p-values for each CVD trait were as follows: major CVD, rs499818,Six associations yielded p < 10 -6 -6-6 -6 p = 6.6 × 10; major CHD, rs2549513, p = 9.7 × 10; AF, rs958546, p = 4.8 × 10; HF: rs740363, p = 8.8 × 10. Of -5 note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 – 1.9 × 10) and major

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