Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

biomed - Benjamin , Wang , Larson , Vasan , Aragam Jayashri , Mitchell , Kathiresan Sekar , Newton-Cheh Christopher , Vita , Keyes , O'Donnell , Levy Daniel

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Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study. Methods We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001. Results We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 . We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10 -5 in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 ( SLIT2 , p = 1.17*10 -7 ); LV systolic dimension, rs10504543 ( KCNB2 , p = 5.18*10 -6 ); LV mass, rs10498091 (p = 5.68*10 -6 ); Left atrial size, rs1935881 ( FAM5C , p = 6.56*10 -6 ); exercise heart rate, rs6847149 ( NOLA1 , p = 2.74*10 -6 ); exercise systolic blood pressure, rs2553268 ( WRN , p = 6.3*10 -6 ); BA baseline flow, rs3814219 ( OBFC1 , 9.48*10 -7 ), and FMD, rs4148686 ( CFTR , p = 1.13*10 -5 ). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; .

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Publié par	biomed
Publié le	01 janvier 2007
Nombre de lectures	434
Langue	English

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BMC Medical Genetics

BioMedCentral

Open Access Research Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study 1,2 1,34 Ramachandran S Vasan*, Martin G Larson, Jayashri Aragam, 5 65,7 Thomas J Wang, Gary F Mitchell, Sekar Kathiresan, Christopher Newton 5,7 21,3 1,8 Cheh ,Joseph A Vita, Michelle J Keyes, Christopher J O'Donnell, 1,8 1,2 Daniel Levyand Emelia J Benjamin

1 2 Address: TheNational Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA,Evans Department of Medicine and 3 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA,Department of Mathematics and Statistics, Boston 4 5 University, Boston, MA, USA,Veterans Administration Hospital, West Roxbury, MA, USA,Cardiology Division, Massachusetts General Hospital, 6 7 Harvard Medical School, Boston, MA, USA,Cardiovascular Engineering, Inc., Waltham, MA, USA,Program in Medical and Population Genetics, 8 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA andNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA Email: Ramachandran S Vasan*  vasan@bu.edu; Martin G Larson  mlarson@bu.edu; Jayashri Aragam  Jayashri.Aragam@va.gov; Thomas J Wang  tjwang@partners.org; Gary F Mitchell  GaryFMitchell@mindspring.com; Sekar Kathiresan  skathiresan1@partners.org; Christopher NewtonCheh  cnewtoncheh@partners.org; Joseph A Vita  jvita@bu.edu; Michelle J Keyes  mjkeyes@bu.edu; Christopher J O'Donnell  codonnell@nih.gov; Daniel Levy  levyd@nih.gov; Emelia J Benjamin  emelia@bu.edu * Corresponding author

Published: 19 September 2007 S<sVuaspaplne</mese<>plt>e<itn>tThtor>dite>R<noe<hicraamF/rnghHam<>etohtl>urtraet00singlp.bww/w:/iomedc1yd0,00uSentraucl.ceosJirqhahipuohtsJ,raeDDi'nOleneLoenvya,llJaRmnedsacBamMie,sxgoi,nhaCDiJrtlseptooeGhrieNtelwtCobn,-hCehaesh,ElClilaE>emjnmaJeBCaroin,SFlineaurosnearhdsnm>p/<ecre>tlti</orited<1--Sfoin231--850<my>rlohpupss/ifidtpe.drpu/l<omp/fd1/74c/noettnent>plem BMC Medical Genetics2007,8doi:10.1186/1471-2350-8-S1-S2(Suppl 1):S2 This article is available from: http://www.biomedcentral.com/1471-2350/8/S1/S2 © 2007 Vasan 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:Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study. Methods:We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency≥0.10, genotype call rate≥0.80, and Hardy-Weinberg equilibrium p≥0.001. Results:We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. -5 Overall, p < 10in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (SLIT2, p = -7 -6-6 1.17*10 );LV systolic dimension, rs10504543 (KCNB2); Left atrial); LV mass, rs10498091 (p = 5.68*10, p = 5.18*10 -6 -6 size, rs1935881 (FAM5C); exercise heart rate, rs6847149 (, p = 6.56*10NOLA1, p = 2.74*10); exercise systolic blood

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