Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation

Floyd H. Chilton, Ani Manichaikul, Chaojie Yang, Timothy D. O'Connor, Laurel M. Johnstone, Sarah Blomquist, Susan M. Schembre, Susan Sergeant, Manja Zec, Michael Y. Tsai, Stephen S. Rich, Susan J. Bridgewater, Rasika A. Mathias, Brian Hallmark

Research output: Contribution to journalReview articlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Article number808054
JournalFrontiers in Nutrition
StatePublished - Feb 8 2022

Bibliographical note

Funding Information:
This work was supported by NCCIH R01 AT008621 and USDA ARZT-1361680-H23-157. The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA), using the Affymetrix Genome-Wide Human SNP Array 6.0.

Publisher Copyright:
Copyright © 2022 Chilton, Manichaikul, Yang, O'Connor, Johnstone, Blomquist, Schembre, Sergeant, Zec, Tsai, Rich, Bridgewater, Mathias and Hallmark.


  • ancestry
  • endocannabinoid
  • fatty acid desaturase
  • gene-diet interaction
  • omega-3 deficiency syndrome
  • omega-3 supplements
  • oxylipins
  • polyunsaturated fatty acid

PubMed: MeSH publication types

  • Journal Article
  • Review


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