Peroxisome proliferator–activated receptor α genetic variation interacts with n–6 and long-chain n–3 fatty acid intake to affect total cholesterol and LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study1,2,3

Background—Peroxisome proliferator–activated receptor-α (PPARA) regulates the expression of genes involved in lipid metabolism. The binding of polyunsaturated fatty acids (PUFAs) to PPARA results in rapid changes in the expression of genes involved in lipid oxidation, with long-chain n–3 fatty acids being potent activators of PPARA. Objective—We evaluated the potential effect modification of PPARA genetic variation on the association between PUFA intake, specifically n–6 and long-chain n–3 fatty acid intakes, and multiple lipid measures in the large biethnic Atherosclerosis Risk in Communities (ARIC) Study. Design—Study participants (10 134 whites and 3480 African Americans) were selected from the ARIC Study—aprospective investigation of atherosclerosis and its clinical sequelae. Multiple linear regression models were used to assess the relation between PPARA genotypes, as well as dietary fatty acid intake, and baseline lipid measures. PPARA-specific effects of variation were assessed by including genotype-by-fatty acid interaction terms in each statistical model. Results—PPARA genotype frequencies were significantly different between whites and African Americans. No significant associations between lipid measures and PPARA genotype were observed in either whites or African Americans. Significant genotype-by-n–6 fatty acid intake interactions were observed only in whites for the 3'untranslated region (UTR) G→A single nucleotide polymorphism (SNP) and total cholesterol (P = 0.03) and LDL cholesterol (P = 0.03). Significant genotype-by-long-chain n–3 fatty acid intake interactions were observed only in African Americans for the 3'UTR C→T SNP and total cholesterol (P = 0.03) and LDL cholesterol (P = 0.02). Conclusions—Findings from the current study suggest that PPARA 3'UTR SNPs modulate the association between lipid concentrations and dietary n–6 fatty acid intake (in whites) and long-chain n–3 fatty acid intake (in African Americans) such that persons with homozygous variant genotypes have significantly lower total cholesterol and LDL-cholesterol measures when consuming higher quantities of n–6 or long-chain n–3 fatty acids. 2Supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. 3Reprints not available. Address correspondence to KA Volcik, Human Genetics Center, University of Texas Health Science Center, 1200 Herman Pressler Drive, Houston, TX 77030. E-mail: kelly.a. volcik@uth.tmc. edu. 1From the Human Genetics Center, University of Texas Health Science Center, Houston, TX (KAV and EB); the Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN(JAN); and the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center and Baylor College of Medicine, Houston, TX (CMB). None of the authors had a personal or financial conflict of interest. NIH Public Access Author Manuscript Am J Clin Nutr. Author manuscript; available in PMC 2009 March 26. Published in final edited form as: Am J Clin Nutr. 2008 June ; 87(6): 1926–1931. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript