rs174547

Transethnic fine-mapping study of glycaemic traits in 26,760 participants (Hispanic/Latino, African, Asian, and Native American) using the Metabochip. Replicated 31/39 fasting glucose and 14/17 fasting insulin loci from European GWAS. Identified two novel secondary signals at G6PC2-rs477224 and GCK-rs2908290, a population-specific signal at G6PC2-rs77719485 in African ancestry, and one novel locus at SLC17A2-rs75862513 for fasting insulin.

A genome-wide association study (GWAS) of serum metabolic quantitative trait loci (mQTLs) in 891 Swedish men identified seven replicating loci (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) with variants showing significant associations with metabolite levels (P = 10^-13 to 10^-91). rs4345897:A>G in PYROXD2 showed the strongest association with caprolactam (P = 2.40 × 10^-91), while rs174549:A>G in FADS1 associated with glycerolphosphocholine (P = 1.91 × 10^-30). Pathway analysis implicated genes with acyl-CoA dehydrogenase activity (ACADS, ACADM, ACAD8, ACAD10, ACAD11, ACOXL) and mQTL SNPs were enriched across GWAS catalog regions.

This study investigated gene-environment interactions between 23 GWAS-identified lipid-associated SNPs and serum vitamins A and E in the National Health and Nutrition Examination Surveys (NHANES), including 5,576 participants across three racial/ethnic groups. Nine significant interactions were identified, with the most significant being APOB rs693×vitamin E associated with LDL-C in Mexican Americans (p=8.94×10⁻⁷). These nine interactions explained only 0.35-1.28% of variation in lipid traits, suggesting that gene-environment interactions account for modest proportions of the missing heritability in lipid metabolism.

A replication study in 21,004 Japanese and 1,203 Mongolian individuals demonstrated that rs174547 in FADS1/FADS2 is associated with plasma lipid profiles in Asian populations. In Japanese, the C allele was significantly associated with increased triglycerides (P=1.5×10⁻⁶, β=0.04 mg/dl per allele) and decreased HDL-C (P=0.03), while in Mongolians, the C allele was strongly associated with decreased LDL-C (P=2.6×10⁻⁶, β=-5.7 mg/dl per allele). The variable effects across populations despite similar genetic backgrounds suggest gene-environment interaction with dietary polyunsaturated fatty acid intake.