The goal of this proposed study is to identify genetic variants that underlie susceptibility to coronary heart disease (CHD) and stroke. Through our candidate gene association studies in several other NHL.BI-funded cohorts, we have identified a number of putative thrombosis and inflammation gene associations with CVD risk. Recently, the CAndidate-gene Association REsource (CARE) study was initiated by NHLBI to support even more extensive genotyping of -2,000 candidate genes (-50,000 SNPs) based on inflammation, thrombosis, and other biologic hypotheses related to CVD in 50,000 participants from eight NHLBI-supported CVD cohort studies. We propose to genotype the same 50K CVD candidate gene SNP panel in 2,500 CHD cases, 2,500 stroke cases, and 2,500 matched controls from the WHI Observational Study (WHI-OS) and WHI hormone trials (WHI-HT). By making efficient use of existing vascular inflammation and thrombosis quantitative phenotype data measured in WHI, combining data with other CARE cohorts, and applying innovative statistical, functional, and computational approaches, we have an unprecedented opportunity to comprehensively assess and validate genotype-phenotype associations related to thrombosis and vascular inflammation pathways and CVD risk. We wil further assess the biologic mechanism of any (validated) candidate gene SNP association by performing candidate SNP genotype - gene expression analysis in silco and in vitro. As a related benefit, the project will also allow identification of interactions between candidate genes and hormone therapy on CVD risk.
