Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

Springer Science and Business Media LLC - Tập 8 - Trang 1-12 - 2007
Christopher J O'Donnell1,2,3, L Adrienne Cupples1,4, Ralph B D'Agostino5, Caroline S Fox1,6,3, Udo Hoffmann7, Shih-Jen Hwang1,3, Erik Ingellson1, Chunyu Liu4, Joanne M Murabito1,8, Joseph F Polak9, Philip A Wolf1,8, Serkalem Demissie4
1The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, USA
2Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, USA
3National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA
4School of Public Health, Boston University, Boston, USA
5Department of Mathematics and Statistics, Boston University, Boston, USA
6Endocrinology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, USA
7Department of Radiology, Massachusetts General Hospital, Boston, USA
8School of Medicine, Boston University, Boston, USA
9Department of Radiology, Tufts-New England Medical Center, Boston, USA

Tóm tắt

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. 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. 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 http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 . 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.

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