Genome-Wide Association Study for Subclinical Atherosclerosis in Major Arterial Territories in the NHLBI's Framingham Heart Study

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dc.contributor.author O'Donnell, Christopher J en_US
dc.contributor.author Cupples, L Adrienne en_US
dc.contributor.author D'Agostino, Ralph B en_US
dc.contributor.author Fox, Caroline S en_US
dc.contributor.author Hoffmann, Udo en_US
dc.contributor.author Hwang, Shih-Jen en_US
dc.contributor.author Ingellson, Erik en_US
dc.contributor.author Liu, Chunyu en_US
dc.contributor.author Murabito, Joanne M en_US
dc.contributor.author Polak, Joseph F en_US
dc.contributor.author Wolf, Philip A en_US
dc.contributor.author Demissie, Serkalem en_US
dc.date.accessioned 2011-12-29T21:02:17Z
dc.date.available 2011-12-29T21:02:17Z
dc.date.copyright 2007 en_US
dc.date.issued 2007-9-19 en_US
dc.identifier.citation O'Donnell, Christopher J, L Adrienne Cupples, Ralph B D'Agostino, Caroline S Fox, Udo Hoffmann, Shih-Jen Hwang, Erik Ingellson, Chunyu Liu, Joanne M Murabito, Joseph F Polak, Philip A Wolf, Serkalem Demissie. "Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study." BMC Medical Genetics 8 (Suppl 1):S4. (2007) en_US
dc.identifier.issn 1471-2350 en_US
dc.identifier.uri http://hdl.handle.net/2144/2502
dc.description.abstract INTRODUCTION: Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study. METHODS: Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multivariable-adjusted residuals in subjects tested for quantitative SCA phenotypes, including ankle-brachial index, coronary artery calcification and abdominal aortic calcification using multi-detector computed tomography, and carotid intimal medial thickness (IMT) using carotid ultrasonography. We evaluated associations of these phenotypes with 70,987 autosomal SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, and Hardy-Weinberg p-value ≥ 0.001 in samples ranging from 673 to 984 subjects, using linear regression with generalized estimating equations (GEE) methodology and family-based association testing (FBAT). Variance components LOD scores were also calculated. RESULTS. There was no association result meeting criteria for genome-wide significance, but our methods identified 11 SNPs with p < 10-5 by GEE and five SNPs with p < 10-5 by FBAT for multivariable-adjusted phenotypes. Among the associated variants were SNPs in or near genes that may be considered candidates for further study, such as rs1376877 (GEE p < 0.000001, located in ABI2) for maximum internal carotid artery IMT and rs4814615 (FBAT p = 0.000003, located in PCSK2) for maximum common carotid artery IMT. Modest significant associations were noted with various SCA phenotypes for variants in previously reported atherosclerosis candidate genes, including NOS3 and ESR1. Associations were also noted of a region on chromosome 9p21 with CAC phenotypes that confirm associations with coronary heart disease and CAC in two recently reported genome-wide association studies. In linkage analyses, several regions of genome-wide linkage were noted, confirming previously reported linkage of internal carotid artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an open-access results resource at. CONCLUSION: The results from this GWAS generate hypotheses regarding several SNPs that may be associated with SCA phenotypes in multiple arterial beds. Given the number of tests conducted, subsequent independent replication in a staged approach is essential to identify genetic variants that may be implicated in atherosclerosis. en_US
dc.description.sponsorship National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (ISI0RR63736-01A1) en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights Copyright 2007 O'Donnell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 2.0 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. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title Genome-Wide Association Study for Subclinical Atherosclerosis in Major Arterial Territories in the NHLBI's Framingham Heart Study en_US
dc.type article en_US
dc.identifier.doi 10.1186/1471-2350-8-S1-S4 en_US
dc.identifier.pubmedid 17903303 en_US
dc.identifier.pmcid 1995605 en_US

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