Abstract 20084: Comprehensive Sequencing and Profiling of 9p21.3 in the Framingham Heart Study Reveals Multiple Associations With Gene Expression, Subclinical and Clinical Cardiovascular Disease
Introduction: The 9p21.3 locus is a strongly replicated region identified by genome-wide association studies (GWAS) for subclinical and clinical cardiovascular disease (CVD) traits. There are few reported efforts to sequence 9p21.3, or to assess copy number variation (CNV) or functional mechanisms, such as gene expression.
Methods: We sequenced a 250kb region (using NHLBI's Resequencing and Genotyping Service) in 281 individuals with myocardial infarction (n=94), high coronary artery calcium (CAC) levels (n=94), or controls with low CAC levels (n=93) from the Framingham Heart Study Offspring cohort. Out of 1,418 sequence variants we identified 126 SNPs with nominal CVD associations for genotyping in 7,030 further individuals in the FHS Offspring and Third Generation cohorts. We proceeded to conduct association analyses for these 126 SNPs with subclinical and clinical CVD phenotypes and risk factors. Additionally, we surveyed CNV at 9p21.3 and assessed genetic associations with gene expression levels of CDKN2A, CDKN2B, and ANRIL in freshly isolated lymphocytes and platelets (n=1,704).
Results: In a large population we found strong associations of 9p21.3 sequence variants with higher CAC levels (P<4.7×10−9), larger abdominal aorta diameters as measured by computed tomography scans (P<5.7×10−4) and increased odds of myocardial infarction (P<7.4×10−5). At the same time we observed no strong association of variants with traditional CVD risk factors. In our sequence data, no common protein-coding variation, variants in splice donor or acceptor sites or CNV events were observed, suggesting these are not major contributors to observed associations at 9p21.3. By contrast strong associations were observed between 9p21.3 variants and lymphocyte gene expression levels for a short isoform of ANRIL (P<4.5×10−9) and for CDKN2B (P<7.3×10−7).
Conclusions: We provide results from a comprehensive sequencing study to follow up a strong GWAS association signal for CVD. Our results suggest regulatory variation affecting ANRIL, CDKN2A and CDKN2B gene expression may influence arterial dysfunction associated with increased risk for disease in some individuals, and that this risk is not primarily mediated through traditional CVD risk factors.
- © 2010 by American Heart Association, Inc.