GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

• Published in: Human molecular genetics Vol. 26; no. 13; pp. 2551 - 2564
• Main Authors: Nongmaithem, Suraj S, Joglekar, Charudatta V, Krishnaveni, Ghattu V, Sahariah, Sirazul A, Ahmad, Meraj, Ramachandran, Swetha, Gandhi, Meera, Chopra, Harsha, Pandit, Anand, Potdar, Ramesh D, H D Fall, Caroline, Yajnik, Chittaranjan S, Chandak, Giriraj R
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2017
• Subjects: Adult; Alleles; Asian Continental Ancestry Group - genetics; Association Studies; Child; Child, Preschool; European Continental Ancestry Group - genetics; Female; Fucosyltransferases - genetics; Fucosyltransferases - metabolism; Gene Frequency - genetics; Genetics, Population; Genome-Wide Association Study; Humans; India; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Vitamin B 12 - blood; Vitamin B 12 - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx071

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 HNF4α, 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.