LAUSR

Abstract Vitamin B12 is an important cofactor in one‐carbon metabolism whose dysregulation is associated with various clinical conditions. Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12 concentrations in Indians. We performed a genome‐wide association study in 1001 healthy participants in the Pune Maternal Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta‐analysis identified new variants, rs3760775 (P = 1.2 × 10−23) and rs78060698 (P = 8.3 × 10−17) in FUT6 to be associated with circulating B12 concentrations. Although in‐silico analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size and the linkage disequilibrium structure of credible set variants with the reported variants suggest population‐specific characteristics in this region. We replicated previously reported variants rs602662, rs601338 in FUT2, rs3760776, rs708686 in FUT6, rs34324219 in TCN1 (all P < 5 × 10−8), rs1131603 in TCN2 (P = 3.4 × 10−5), rs12780845 in CUBN (P = 3.0 × 10−3) and rs2270655 in MMAA (P = 2.0 × 10−3). Circulating B12 concentrations in the PMNS and Parthenon study showed a significant decline with increasing age (P < 0.001), however, the genetic contribution to B12 concentrations remained constant. Luciferase reporter and electrophoretic‐mobility shift assay for the FUT6 variant rs78060698 using HepG2 cell line demonstrated strong allele‐specific promoter and enhancer activity and differential binding of HNF4&agr;, a key regulator of expression of various fucosyltransferases. Hence, the rs78060698 variant, through regulation of fucosylation may control intestinal host‐microbial interaction which could influence B12 concentrations. Our results suggest that in addition to established genetic variants, population‐specific variants are important in determining plasma B12 concentrations.