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

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?

SUBMITTER: Nongmaithem SS

PROVIDER: S-EPMC5886186 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Nongmaithem Suraj S SS Joglekar Charudatta V CV Krishnaveni Ghattu V GV Sahariah Sirazul A SA Ahmad Meraj M Ramachandran Swetha S Gandhi Meera M Chopra Harsha H Pandit Anand A Potdar Ramesh D RD H D Fall Caroline C Yajnik Chittaranjan S CS Chandak Giriraj R GR

Human molecular genetics 20170701 13

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 var ...[more]

PMID: 28334792

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Project description:Abstract Objectives Background: The FUT2 gene is responsible for the secretion of ABO blood type antigens into the body fluids (saliva, mucous, urine, tears, breast milk, sweat, and semen). Those who secrete the antigens into body fluids are call secretors, those who do not are called non-secretors. Hypothesis: GWAS studies have reported FUT gene variants to be associated with circulating vitamin-B12 (Vit-B12) concentrations. Missense mutations in the FUT2 gene result in a non-secretor phenotype. Thus, the secretory status of an individual may affect circulating vitamin-B12 concentrations over and above the genotype. Methods Materials and Methods: We included 780 participants (271 children, 282 mothers, and 227 fathers) from Pune Maternal Nutrition Study (PMNS). We measured the secretor status of individuals in saliva by hemagglutination test. A total of eight genetic variants including six SNPs from the FUT2 gene (rs492602, rs681343, rs281377, rs601338, rs1800027, and rs602662) and two SNPs from the FUT6 gene (rs3760776 and rs3760775) from our previous GWAS study were correlated with circulating vitamin-B12 levels. We tested the associations of FUT gene variants with secretor status phenotype and of the secretor phenotype with circulating vit-B12, folate, and ferritin concentrations in addition to H.pylori antibody levels. Results Results and Discussion: We found 33% of participants were non-secretors compared to 20% reported in Western Caucasian populations. Non-secretors had higher vitamin-B12 concentrations but not of folate and ferritin, vitamin-B12 associations were over and above FUT genotypes. Non-secretors showed a higher response to Vit-B12 supplementation. We found a FUT2 haplotype () to be strongly associated with Vit-B12 concentrations and non-secretor status. Non-secretors had lower H.pylori antibody concentrations. FUT6 genotype and haplotype were associated with Vit-B12 concentrations but not with secretor status and H.pylori antibody levels. Conclusions Our data suggest that secretor status may influence Vit-B12 concentrations through susceptibility to H.pylori infection and possibly other gut microbiota. A higher frequency of non-secretors in Indians could offer a selective advantage against Vit-B12 deficiency. Funding Sources BBSRC, UK; MRC, UK; WELLCOME TRUST, UK; DBT, India; ICMR India

Project description:Background:Low vitamin B12 concentrations have been associated with major clinical outcomes, including adiposity, in Indian populations. The Fat mass and obesity-associated gene (FTO) is an established obesity-susceptibility locus; however, it remains unknown whether it influences vitamin B12 status. Hence, we investigated the association of two previously studied FTO polymorphisms with vitamin B12 concentrations and metabolic disease-related outcomes and examined whether these associations were modified by dietary factors and physical activity. Methods:A total of 176 individuals with type 2 diabetes, 152 with pre-diabetes, and 220 normal glucose-tolerant individuals were randomly selected from the Chennai Urban Rural Epidemiology Study. Anthropometric, clinical, and biochemical investigations, which included body mass index (BMI), waist circumference, vitamin B12, homocysteine, and folic acid were measured. A validated food frequency questionnaire was used for dietary assessment and self-reported physical activity measures were collected. An unweighted genetic risk score (GRS) was calculated for two FTO single-nucleotide polymorphisms (rs8050136 and rs2388405) by summation of the number of risk alleles for obesity. Interaction analyses were performed by including the interaction terms in the regression model. Results:The GRS was significantly associated with increased BMI (P =?0.009) and risk of obesity (P?=?0.023). Individuals carrying more than one risk allele for the GRS had 13.13% lower vitamin B12 concentrations, compared to individuals carrying zero risk alleles (P?=?0.018). No associations between the GRS and folic acid and homocysteine concentrations were observed. Furthermore, no statistically significant GRS-diet or GRS-physical activity interactions with vitamin B12, folic acid, homocysteine or metabolic-disease outcomes were observed. Conclusion:The study shows for the first time that a genetic risk score using two FTO SNPs is associated with lower vitamin B12 concentrations; however, we did not identify any evidence for the influence of lifestyle factors on this association. Further replication studies in larger cohorts are warranted to investigate the association between the GRS and vitamin B12 concentrations.

Project description:Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited.A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort.Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10-31) and ABCG2 (rs2231142, combined P = 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10-2 and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females.Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.

Project description:Genome-wide association studies have successfully identified over 70 loci associated with the risk of type 2 diabetes mellitus (T2DM) in multiple populations of European ancestry. However, the risk attributable to an individual variant is modest and does not yet provide convincing evidence for clinical utility. Association between these established genetic variants and T2DM in general populations is hitherto understudied in the isolated populations, such as the Uyghurs, resident in Hetian, far southern Xinjiang Uyghur Autonomous Region, China. In this case-control study, we genotyped 13 single-nucleotide polymorphisms (SNPs) at 10 genes associated with diabetes in 130 cases with T2DM and 135 healthy controls of Uyghur, a Chinese minority ethnic group. Three of the 13 SNPs demonstrated significant association with T2DM in the Uyghur population. There were significant differences between the T2DM patients and controls in the risk allele distributions of rs3792267 (CAPN10) (P = 0.002), rs1501299 (APM1) (P = 0.017), and rs3760776 (FUT6) (P = 0.031). Allelic carriers of rs3792267-A, rs1501299-T, and rs3760776-T had a 2.24-fold [OR (95% CI): 1.35-3.71], 0.59-fold [OR (95% CI): 0.39-0.91], 0.57-fold [OR (95% CI): 0.34-0.95] increased risk for T2DM respectively. We further confirmed that the cumulative risk allelic scores calculated from the 13 susceptibility loci for T2DM differed significantly between the T2DM patients and controls (P = 0.001), and the effect of obesity/overweight on T2DM was only observed in the subjects with a combined risk allelic score under a value of 17. This study observed that the SNPs rs3792267 in CAPN10, rs1501299 in APM1, and rs3760776 in FUT6 might serve as potential susceptible biomarkers for T2DM in Uyghurs. The cumulative risk allelic scores of multiple loci with modest individual effects are also significant risk factors in Uyghurs for T2DM, particularly among non-obese individuals. This is the first investigation having observed/found genetic variations on genetic loci functionally linked with glycosylation associated with the risk of T2DM in a Uyghur population.

Dataset Information

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

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

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