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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
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Srinivas, Pothur R
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Li, Changwei; Kim, Yun Kyoung; Dorajoo, Rajkumar et al. (2017) Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. Circ Cardiovasc Genet 10:e001527
Hu, Yao; Tanaka, Toshiko; Zhu, Jingwen et al. (2017) Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations. J Lipid Res 58:974-981
Peralta, Carmen A; Bibbins-Domingo, Kirsten; Vittinghoff, Eric et al. (2016) APOL1 Genotype and Race Differences in Incident Albuminuria and Renal Function Decline. J Am Soc Nephrol 27:887-93
Manichaikul, Ani; Wang, Xin-Qun; Zhao, Wei et al. (2016) Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis. J Lipid Res 57:433-42
Liu, Chunyu; Kraja, Aldi T; Smith, Jennifer A et al. (2016) Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat Genet 48:1162-70
Lemaitre, Rozenn N; King, Irena B; Kabagambe, Edmond K et al. (2015) Genetic loci associated with circulating levels of very long-chain saturated fatty acids. J Lipid Res 56:176-84
Cornelis, Marilyn C; Fornage, Myriam; Foy, Millennia et al. (2015) Genome-wide association study of selenium concentrations. Hum Mol Genet 24:1469-77
Verhaaren, Benjamin F J; Debette, St├ęphanie; Bis, Joshua C et al. (2015) Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ Cardiovasc Genet 8:398-409
Hansen, J G; Gao, W; Dupuis, J et al. (2015) Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. Respir Res 16:81
Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897

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