Abstract MP67: Fatty Acid Desaturase Gene-induced Omega-3 Deficiency In Amerindian-Ancestry Hispanic Populations

Hispanic populations in the US have increased risk of obesity, elevated circulating triglycerides, nonalcoholic fatty liver disease, and diabetes. Our previous studies suggest that ancestry-related differences in the frequency of variants in the fatty acid desaturase (FADS)gene cluster in the context of the modern Western diet can lead to inadequate circulating and tissues levels of n-3 long-chain (LC-; ≥ 20 carbons) polyunsaturated fatty acids (PUFA); these deficiencies in turn have the capacity to increase metabolic disease risk. Specifically, we and others have demonstrated Amerindian (AI)-Ancestry populations have high frequencies of FADSgene variants that may lead to less efficient n-3 LC-PUFA biosynthesis. To test this hypothesis, concentrations of fatty acids, including LC-PUFAs in plasma phospholipids were analyzed in 1,102 Hispanic American participants from Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which represent six Hispanic subgroups based on self-reported region of origin: Central America, South America, Mexico, Cuba, Dominican Republic, and Puerto Rico. These data revealed a striking inverse relationship between genome-wide AI-ancestry and levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additional analyses revealed that the genotype at FADSSNP rs174537, for which the frequency of the T allele increases with AI-ancestry, could primarily explain the associations. There also was a strong association between the number of T alleles (additive model) at rs174537 and circulating triglycerides (18.5 mg/dL per T allele; P=2.0 x 10-5) as well as an important marker of vascular inflammation sICAM-1 (β=12.7 ng/mL, P=0.02). We also genotyped the FADSSNP, rs174537, in a separate adult Arizona Hispanic cohort (Arizona Insulin Resistance [AIR] registry) and compared the FADSgenotypic frequencies with other racial/ethnic groups. Importantly, the TT genotype associated with limited LC-PUFA biosynthesis ranges from <1% in African-Ancestry populations to 40.2% in AI-Ancestry Hispanics in the AIR Registry, with ~11 % in European-Ancestry populations. These data demonstrate that high AI-ancestry populations have a dramatically higher frequency of the TT genotype versus African and European populations. Importantly similar to MESA, there also was a significant association between the number of T alleles and plasma triglycerides (p = 0.0036; GG = 125±8.18 mg/dl, GT = 135±5.63 mg/dl, TT = 143±5.58 mg/dl) again suggesting the AI-associated TT genotype places this population at higher risk of hypertriglyceridemia. Together, these data reveal that FADSgene*dietary PUFA interactions give rise to n-3 LC-PUFA deficiencies and may enhance metabolic and inflammatory diseases in a large proportion of individuals in AI-Ancestry Hispanic populations.