GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians.
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.
Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500 007, India.
Suraj S
SS
Nongmaithem
Diabetes Unit, King Edward Memorial Hospital and Research Centre, Rasta Peth, Pune, Maharashtra 411 011, India.
Charudatta V
CV
Joglekar
Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, Karnataka 570 021, India.
Ghattu V
GV
Krishnaveni
Research Department, Centre for the Study of Social Change, Mumbai, Maharashtra 400 051, India.
Sirazul A
SA
Sahariah
Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500 007, India.
Meraj
M
Ahmad
Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500 007, India.
Swetha
S
Ramachandran
Research Department, Centre for the Study of Social Change, Mumbai, Maharashtra 400 051, India.
Meera
M
Gandhi
Research Department, Centre for the Study of Social Change, Mumbai, Maharashtra 400 051, India.
Harsha
H
Chopra
Department of Pediatrics, King Edward Memorial Hospital and Research Centre, Rasta Peth, Pune, Maharashtra 411 011, India.
Anand
A
Pandit
Research Department, Centre for the Study of Social Change, Mumbai, Maharashtra 400 051, India.
Ramesh D
RD
Potdar
Research Department, Centre for the Study of Social Change, Mumbai, Maharashtra 400 051, India.|MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Caroline
C
H D Fall
Diabetes Unit, King Edward Memorial Hospital and Research Centre, Rasta Peth, Pune, Maharashtra 411 011, India.
Chittaranjan S
CS
Yajnik
Genomic Research on Complex Diseases (GRC Group), CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500 007, India.|Human Genetics Unit, Genome Institute of Singapore, Biopolis, 138 672, Singapore.
Giriraj R
GR
Chandak
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency / Q000235:genetics; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D007194:India; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014805:Vitamin B 12 / Q000097:blood / Q000378:metabolism*; D044465:White People / Q000235:genetics
D005647:Fucosyltransferases; C515956:FUT6 protein, human; D014805:Vitamin B 12