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The widespread availability of high throughput methods have enabled rapid advances in establishing associations between single nucleotide polymorphisms and health outcomes.Commonly used SNPs were generally chosen to track heritage blocks not connected to causing differences in genetic function via GWAS.Diversity in gene function extends beyond SNPs to other genetic elements including insertion-deletions(Indels).Endogenous PUFA levels are regulated by diet PUFA.The fatty acid desaturase(FADS)gene cluster has been identified in dozens of GWAS as associated with health and biochemical outcomes.We sought to identify causal variants that control FADS expression and PUFA levels.First computationally we searched the International Hapmap Project database in Japanese participants for expression quantitative trait locus(eQTL)and identified a highly significant region in intron 1 of FADS2 associated with lower expression of FADS1 in the minor allele,and identified predicted consensus biding site for two transcription factors,PPARg and SREBP,and hypothesized that polymorphisms nearby would affect binding.Second lymphoblasts homozygous for the major and minor alleles were cultured leading to the discovery that FADS1 expression is lower in the minor vs major haplotype,and that expression of both FADS1 and FADS2 was strongly modulated by SREBP but not PPARg binding drugs.We sequenced and discovered a 22 bp Indel 137 bp from the SRE: the minor allele is a deletion and the major allele an insertion.Returning to computation with the 1000 genome database we showed that the Indel status causes positive selection related to ancestral diet.Third we compared Indel genotype (rs66698963)from 199 individuals in Kansas City and 1,500 in Beijing against the circulating PUFA and find that circulating arachidonic acid and all omega-3 PUFA are determined genotype.Taken together,these data strongly support rs66698963 Indel as a causal locus in determining arachidonic acid status,with broad implications for inflammation,thrombosis,and related metabolic risk factors.We suggest that genotype at this locus should be considered in all studies of LCPUFA interventions