A 22 bp FADS2 Insertion‐Deletion (Indel) Polymorphism Influences Arachidonic Acid Status

Abstract

IntroductionThe fatty acid desaturase 2 (FADS2) gene product catalyzes a key step in the biosynthesis of biologically active long chain polyunsaturated fatty acids (LCPUFA). The rs66698963 a 22 bp polymorphic insertion‐deletion (Indel) is associated with basal expression of FADS1 which mediates the Δ5‐desaturation of dihomo‐gamma‐linolenic acid to arachidonic acid (20:3n‐6→20:4n‐6), as well as coordinated induction of FADS1 and FADS2 expression in vitro. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage.MethodsA total of 234 individuals of a primarily vegetarian Indian population and 311 individuals from the U.S were genotyped. Evolutionary analysis testing for positive selection on the FADS region was performed using genetic variations data from the 1000 Genomes Project (1000GP). Functional analysis of rs66698963 genotypes and fatty acid levels was evaluated in a subset of the U.S. population.ResultsA much higher I/I genotype frequency was found in Indians (68%) than in the U.S. (18%). Data from 1000 Genomes Project confirmed our observation and revealed a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Evolutionary analyses revealed for the first time signals of positive selection around rs66698963 in only South Asians. Basal plasma phospholipid arachidonic acid status was 8% greater in I/I compared to D/D individuals. The biochemical pathway product‐precursor difference, arachidonic acid minus linoleic acid, was 31% and 13% greater for I/I and I/D compared to D/D, respectively.ConclusionOur study is consistent with previous in vitro data suggesting that the insertion allele enhances n‐6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant‐based diet practice.Support or Funding InformationR01 AT007003