? ? The Amish Heredity and Phenotype Intervention (HAPI) Heart Study is one of four studies that constitute the NHLBI PROGENI Network. The overall goal of this project is to identify genes that interact with specific environmental exposures to influence risk factors for cardiovascular disease (CVD). In 900 Amish subjects, we obtained baseline CVD phenotypes and response phenotypes to four short-term interventions, including blood pressure (BP) response to cold pressor stress, BP response to high and low salt diets, triglyceride response to a high fat feeding, and platelet response to aspirin therapy. Genotyping of over 250,000 single nucleotide polymorphisms (SNPs)(Affymetrix Nsp chip) and SNPs in candidate genes for response phenotypes in these subjects are underway and will be completed by September 2006. In this Limited Competition Renewal application, we propose to continue and extend our analyses of this unique dataset. First, we will characterize the genetic epidemiology of the CVD response phenotypes to the four short-term interventions. Second, we will carry out a genome-wide linkage scan of response phenotypes to the four interventions using a subset of SNPs genotyped from the 250K SNP chip in 900 Amish HAPI Heart Study participants. We will then compare regions of linkage with those identified from analysis of the same phenotypes in other PROGENI studies. Finally, we will conduct genetic association analyses of response phenotypes to evaluate whether (a) SNPs that fall within regions under the linkage peaks identified are associated with variation in response phenotypes; (b) single SNPs and/or haplotypes genotyped in a small set of carefully targeted candidate genes are associated with variation in response phenotypes; (c) SNPs and/or haplotypes found to be associated with response phenotypes in other PROGENI studies are also associated with the same phenotype in the Amish HAPI Heart Study; and (d) response phenotype associated SNPs identified in (a) and (b) above are also associated with variation in subclinical atherosclerosis as measured by carotid intimal media thickness (IMT). These discoveries may lead to new insights into the pathophysiology of CVD, more effective strategies for risk stratification and prevention, and novel targets for therapeutic interventions, thus decreasing morbidity and mortality in millions of middle age and elderly Americans. ? ? ?
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