Impact of Variation in FADS and ELOVL on Polyunsaturated Fatty Acid Metabolism and Cardiometabolic Risk Factors in Mexican American and American Indian Populations

Abstract

Over the last 75 years, significant shifts in dietary patterns have mirrored the rise of non-communicable diseases, which account for approximately 75% of deaths in developed countries. Cardiometabolic diseases (CMD) remain the leading cause of death globally, with disparities particularly evident among various racial/ethnic minority groups in the United States (US) . These disparities are highly impacted by the Modern Western Diet (MWD), differential nutrient metabolism, and destructive gene-diet interactions. A decade of nutrigenomics research has highlighted how ancestry-related genetic variation interacts with the consumption of 18-carbon (18C) essential omega-6 and -3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA), to influence molecular and clinical biomarkers. Specifically, variations in the fatty acid desaturases (FADS1/2/3) cluster, crucial for determining the efficiency for converting dietary 18C alpha-linolenic acid (ALA) and linoleic acid (LA) into long chain (>=20) highly unsaturated fatty acids (HUFA), are linked to levels of cardiometabolic (CMD) markers. These genetic variations alter the balance of n-6 and n-3 HUFAs and the production of their respective bioactive oxylipins. Previous research established that African-ancestry populations primarily carry two copies of variants linked to the FADS “derived” haplotype (DH) associated with the efficient conversion of 18C PUFA to HUFAs. The "ancestral" haplotype (AH), linked to reduced conversion capacity is prevalent in Hispanic Americans and nearly fixed in Indigenous American populations. This dissertation investigates the impact of FADS and elongase (ELOVL5/2, responsible for PUFA and HUFA elongation) variants on CMD risk in Latinos of Mexican Ancestry (LAM) and American Indians (AI), employing regression models with covariate adjustments to explore associations between genotypes and PUFAs, HUFAs and CMD markers. Individuals carrying two copies of AH variants (~50% in LAM and ~78% in AI) exhibited significantly lower HUFA levels (especially n-3 HUFAs) altered levels of triglycerides, VLDL, HDL, fasting and 2 hr glucose, and anthropometrics measures. For example, LAM homozygous for AH variants also exhibited a ~40% increase in insulin and HOMA-IR, while AI individuals homozygous at AH variants exhibited a ~34% increase in HOMA-IR and an 18% increase in 2 hr glucose, compared to AI individuals with two copies DH variants. These findings highlight the role of genetic variation (particularly within the FADS cluster) in driving HUFA effects and CMD phenotypes in at-risk populations, and suggests the need for robust precision nutrition-based HUFA supplementation trials to mitigate aspects of CMD risk arising from this FADS gene-by-dietary PUFA interaction.