Genetic modification of PUFA biosynthesis and CHD

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DESCRIPTION (provided by applicant): Polyunsaturated fatty acids (PUFA) exert vital functions on membrane structure, cell signaling, and regulation of gene expression. PUFA are the precursors of several different eicosanoids, which have multiple roles in inflammation, regulation of blood pressure, and blood clotting, among many other functions. Through these functions, PUFA are undoubtedly linked to the prevention of development of coronary heart disease (CHD). Linoleic (n-6) and alpha-linolenic acid (n-3) are essential fatty acids (FA) that can be converted into long- chain PUFA through elongation, desaturation, and strong feedback regulated by transcription factors, sterol desaturases enzymes involved in this biosynthetic pathway are regulated by transcription factors, sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferators-activated receptor-alpha (PPAR-alpha). We hypothesize that mutations in these genes affect FA biosynthesis and risk of CHD. Our overall objective is to assess individual variability in the effect of dietary PUFA on Ml, by examining genes involved in their biosynthetic pathway. We will study 2,150 case survivors of Ml and 2,150 population-based controls from out ongoing study. Specific hypothesis will examine the genetic mechanisms that link intake of FA [1) n-3 FAs: alpha-linolenic acid, eicosapentaenoic acid (EPA), and docsahexaenoic acid, (DMA); 2) n-6 FAs: linoleic acid, and arachidonic acid, and 3) trans FA] to risk of Ml. The proposed genes include: fatty acid desaturase (FADS)2 (delta6-desaturase), FADS1 (delta5-desaturase), and FADS3, ELOVL-1,2,3,4,5,6,7 (7 elongase genes), PPAR-alpha, and SREBP-1c. Further hypothesis will be tested with other genes involved in the synthesis of eicosanoids from arachidonic acid and EPA: cycloxygenase(COX)-2, S-lypoxygenase(LOX), and cytochrome P450 2J2 (CYP2J2). FAs in adipose tissue will be used as biomarkers of intake. Biochemical measurements, dietary data, and general information are available for this population. The proposed study offers and unusual opportunity to expand our understanding of how genetic and environmental conditions can influence CHD. The diet of the population offers a wide range in variation of all the major types of FAs, particularly with low ranges of saturated fat and n-3 FAs represented. This strengthens evaluation of risk, and application to current dietary goals. The large number of SNPs proposed for final analysis will add to the resolution and power to identify the genes that underlie CHD.