Grant Abstract: Addressing Diet-Induced Health Disparities with Precision Nutrition and Omega-3 Fatty Acids

Grant Number: 2R01AT008621-07
PI Name: Chilton
Project Title: Addressing Diet-Induced Health Disparities with Precision Nutrition and Omega-3 Fatty Acids

Abstract: The cardioprotective benefits of omega 3 (n-3) highly unsaturated fatty acids (HUFA) have been called into question due to conflicting results of clinical trials. Our work over the past decade has revealed that genetic variation in the fatty acid desaturase 1 (FADS1) gene and race may be significant drivers of the effectiveness of n-3 HUFA supplementation. FADS1 is the rate limiting step in the conversion of the dietary n-6 and n-3 polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, to n-6 and n-3 HUFAs, including arachidonic acid (ARA, n-6), eicosapentaenoic acid (EPA, n-3), docosahexaenoic acid (DHA, n-3), and their biologically active oxylipin metabolites. The importance of genetic variation encoding the desaturase steps in this pathway was recently highlighted when the FADS1-FADS2 gene cluster was identified as the largest multimorbidity cluster in the entire human genome with over 40 phenotypes related to lipid and fat metabolism, inflammatory disorders, and multiple cancers. A central discovery from our work and others is the differential disease mechanism-relevant synthesis of HUFAs and metabolism to bioactive lipids across racial groups. This is perhaps most apparent when comparing European Americans (EuAm) and African Americans (AfAm) in that AfAm have much higher frequencies of FADS1 variants that are associated with the efficient conversion of dietary LA to ARA and its pro-inflammatory/pro-thrombotic oxylipins. Clinical evidence in support of this work comes from our re-analysis of the VITAL n-3 HUFA supplementation trial which demonstrated that AfAm, but not EuAm may have strongly benefitted from n-3 supplementation, with an ~ 80% reduction in myocardial infarction (MI). We then applied two machine learning methods to matched data from AfAm and EuAm VITAL participants and found strong evidence that n-3 supplementation significantly decreased MI only in AfAm with the odds ratio between the treatment and placebo groups of 0.178 (95% CI [0.046 0.69]). These data lead to this proposal’s central hypothesis that gene-diet interactions drive an imbalance in ARA versus EPA and DHA and their oxylipin products particularly in AfAm. We postulate that optimally-dosed n-3 HUFA supplementation will decrease the ratio of ARA to EPA and DHA, providing a major benefit to AfAm. We propose a two-site randomized, double-blind, placebo-controlled, crossover n-3 HUFA supplementation trial that leverages the extraordinary diversity and community-based recruitment experiences of our partnering institutions to test our hypothesis. Specifically, we will supplement AfAm and EuAm participants stratified by FADS1 genotype with EPA-enriched n-3 HUFAs and evaluate changes in the balance of HUFA-containing lipids and oxylipin products, as well as inflammatory and clinical biomarkers linked to CVD. This trial will provide critical missing evidence for genetic and racial heterogeneity and resulting differential biological response to n-3 HUFAs in AfAm and EuAm. These data are essential to the future design of definitive precision nutrition clinical trials to prevent chronic diseases and reduce health disparities. PUBLIC HEALTH RELEVANCE: Dietary fatty acid supplementation could be the most potentially effective dietary strategies to reduce critical diet- related health disparities; however, the under-representation of African American adults in studies of omega-3 (n-3) highly unsaturated fatty acid (HUFA) supplementation has obscured the staggering reductions in cardiovascular disease risk and other chronic disease outcome benefits in this historically underserved population. Our prior work shows that differences in genetic makeup leads to differential response to n-3-HUFA supplementation for African Americans and Non-Hispanic Whites. Here we propose to recruit African Americans and non-Hispanic Whites based on their genetic makeup, provide HUFA supplementation, and see if we can improve markers of inflammation and cardiovascular and metabolic disease risk.

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