Atherosclerosis is the primary cause of coronary heart disease, which contributes to 1 of every 5 deaths and exacts a financial toll of over $200 billion annually in the US. Although complex relationships between genotype and phenotype have been recognized in the etiology of atherosclerosis, genetic studies have largely focused on a """"""""locus-by-locus"""""""" strategy. When multiple genes are functionally related - for example, through a common biologic pathway - mutations at any of several genes of that pathway may contribute to disease risk. Collective or joint testing of a set of functionally related candidate genes may dramatically improve the power of genetic association studies of complex disease. CYP450-derived eicosanoids play an important role in cardiovascular function and may be intimately involved in pathogenesis of atherosclerosis. In this application, we will use new information on genome sequence variation derived from the International HapMap project and other public or private efforts, and resources from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study to evaluate the associations of common patterns of variation in genes of the CYP450-derived eicosanoids pathway with subclinical atherosclerosis and its risk/actors in young African-Americans and Whites. For each racial group, a set of maximally informative single nucleotide polymorphisms will be genotyped in each of 20 candidate genes involved in the biosynthesis metabolism of CYP450-derived eicosanoids. Common patterns of variation (multi-locus genotypes and haplotypes) in these genes will then be assessed for their associations with 2 non-invasive measures of subclinical atherosclerosis: presence of coronary calcified plaque (CAC) and carotid intima media thickening (IMT). Dietary polyunsaturated fatty acids (PUFAs) are efficient substrates of the CYP450 enzymes and may modulate the production of endogenous CYP450-derived eicosanoids. The proposed study provides the opportunity to efficiently evaluate the effects of modifiable environmental factors - dietary PUFAs - on the relationships between patterns of variation in novel candidate genes and risk for subclinical atherosclerosis. The significance of the proposed research lies in its potential to identify new mechanisms implicated in the development of atherosclerosis, contributing to a better understanding of disease etiology and opening new avenues for the development of novel therapeutic targets and nutritional interventions.
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