Abstract
Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS “derived” haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an “ancestral” haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.
Highlights
Unsaturated fatty acids (HUFA)—polyunsaturated fatty acids (PUFA) with ≥20 carbons and ≥3 double bonds—and signaling metabolites derived from them play key roles in inflammation and thrombosis that contribute to numerous medical conditions including cardiovascular disease (CVD), Alzheimer’s disease (AD), type 2 diabetes, autoimmunity, cancer, hypersensitivity disorders, skin and digestive disorders, and infectious disease such as COVID-19 [1, 2]
We have demonstrated that the method used to express levels of PUFA and Highly unsaturated fatty acids (HUFA) can affect the magnitude and direction of associations with blood lipids [24], and it remains to be seen whether this impacts coronary heart disease (CHD) endpoints or mortality risk
We found a similar impact on flux of 82% measuring dihomo gamma linolenic acid (DGLA) and arachidonic acid (ARA) levels when comparing the GG and the TT genotypes for the variant rs174537 [37] near FADS1/2
Summary
Unsaturated fatty acids (HUFA)—polyunsaturated fatty acids (PUFA) with ≥20 carbons and ≥3 double bonds—and signaling metabolites derived from them play key roles in inflammation and thrombosis that contribute to numerous medical conditions including cardiovascular disease (CVD), Alzheimer’s disease (AD), type 2 diabetes, autoimmunity, cancer, hypersensitivity disorders, skin and digestive disorders, and infectious disease such as COVID-19 [1, 2]. With regard to African ancestry populations, data from the studies raised questions as to the impact of a Western diet (containing 6–8% LA and a LA to ALA ratio >10:1) on these populations, which have a high frequency of alleles associated with efficient HUFA biosynthesis Both observational genetic association studies suggesting potential interactions (genetic allele frequencies do not completely explain population differences), and recent clinical trials (offering empirical evidence of gene-nutrient interactions) suggest that this gene-diet interaction would lead to a marked increase in the production of ARA relative to DGLA as well as reducing n-3 HUFA including EPA, DPA and DHA by about 50% in AfAm and other Africanancestry populations [1, 37, 66, 67]. Considering individual genotypes at FADS and other loci will likely lead to personalized supplementation and dietary recommendations
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