期刊
HUMAN MOLECULAR GENETICS
卷 26, 期 13, 页码 2551-2564出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx071
关键词
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资金
- Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, India
- Wellcome Trust, London, UK
- Medical Research Council, London, UK
- Department for International Development, UK
- Parthenon Trust, Switzerland
- ICICI Bank, Social Initiatives Group
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 x 10(-23)) and rs78060698 (P = 8.3 x 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 x 10(-8)), rs1131603 in TCN2 (P = 3.4 x 10(-5)), rs12780845 in CUBN (P = 3.0 x 10(-3)) and rs2270655 in MMAA (P = 2.0 x 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 allelespecific promoter and enhancer activity and differential binding of HNF4 alpha, 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.
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