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Open Access 01-09-2007 | Research

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

Authors: Christopher J O'Donnell, 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

Published in: BMC Medical Genetics | Special Issue 1/2007

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

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.

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Title: Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study
Authors: Christopher J O'Donnell
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
Publication date: 01-09-2007
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue Special Issue 1/2007
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-8-S1-S4

At a glance: The STEP trials

Springer Medicine

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

Abstract

Introduction

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

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