Component 1, E. Boerwinkle, PI, is an integral part of this Collaborative Research Project grant entitled Modeling DNA Diversity in Reverse Cholesterol Transport involving two other components: population genetic analysis (Component 2, A. Clark, PI) and genotype-phenotype studies (Component 3,C. Sing, PI). Although there is a division of labor among components for practical and institutional purposes, the co-investigators and consultants engaged in this project will work as a team to develop resources to address one of the most complex and challenging problems in medicine, how is DNA sequence variation related to variation in human health in the population at large? Component 1 will generate population-based genotype information for 62 genes that are known to modulate measures of reverse cholesterol transport (RCT). To accomplish this goal we will: 1) build a bioinformatics resource for the RCT pathway, 2) determine the common SNP haplotypes for these 62 RCT genes, 3) use the haplotype information to guide in the selection of genotyping 6-10 SNPs per gene (approximately 600 DNA sequence variations) that will be genotyped in a population-based sample of 2007 African-Americans and 2139 European-Americans from the Coronary Artery Risk Development in Young Adults (CARDIA) study and 4) follow-up results from the survey of RCT genes to identify all SNPs in the subset of genes that show associations with RCT phenotypes. Component 1will resequence genes that show associations in the 40 hybrid cell lines to identify SNPs (and phase) for high-throughput genotyping of the selected subset of genes in the population-based CARDIA sample.
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