The goal of Project 3 is to identify genes that influence quantitative phenotypes related to dyslipidemia, oxidative damage and hypertension in the baboon model. Methods: We will use two approaches to identify these genes. First, we will use chromosomal region specific gene expression profiling, positional cloning and statistical genomic analysis to identify genes encoding dyslipidemia, oxidative damage and hypertension quantitative trait loci (QTLs). These studies will be conducted for previously identified QTLs and for two new QTLs identified in the pedigreed, genotyped, phenotyped baboons at the SNPRC using biopsied tissues collected after basal and high-cholesterol, high-fat (HCHF) diets. Second, we will use whole genome expression profiling on biopsied tissue RNA from the pedigreed baboons to identify candidate genes and gene networks that regulate quantitative phenotypes related to dyslipidemia, oxidative damage and hypertension. The following Specific Aims will be completed to achieve this goal: 1) To identify and prioritize candidate genes encoding dyslipidemia, oxidative damage and hypertension QTLs. 2) To identify candidate genes and candidate gene networks relevant to dyslipidemia by performing whole genome expression profiling for pedigreed baboons fed the HCHF diet long-term. 3) To determine which of the top priority candidate genes identified in Aims 1 and 2 actually influence measures of dyslipidemia, oxidative damage and hypertension by conducting statistical genomic analyses. 4) To confirm by in vitro functional assays the roles of sequence variants in the regulation of phenotypic variation for five high priority candidate genes identified in Aim 3. 5) For each baboon gene analyzed in Aim 4, to identify statistical functional variants in the human homologue for the same class of polymorphisms. Expected outcomes from these studies include: 1) Identification of genes that regulate five dyslipidemia, oxidative damage and/or hypertension quantitative traits in defined chromosomal regions; 2) Identification of the relationships between these genes that are relevant to cardiovascular disease phenotypic variation; and 3) Identification of polymorphisms that encode the observed phenotypic variation in these genes. Significance: Results from this study will define genetic mechanisms of cardiovascular disease and provide targets for interventions to prevent cardiovascular disease.
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