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The genetic determinants of circulating C3-epimers of 25-hydroxyvitamin D.

ABSTRACT: Background:The complexity of vitamin D metabolites especially the contribution of C3-epimers of 25-hydroxyvitamin D (C3-epimers) in human sera remains unclear. We hypothesized that genetic polymorphisms in the vitamin D-related gene pathway contribute to variation in C3-epimer levels. Therefore, we investigated candidate single nucleotide polymorphisms (SNPs) concerning C3-epimer levels. Methods:The candidate SNPs, including DHCR7/NADSYN1 (rs12785878), CYP2R1 (rs2060793) and GC (rs2282679), were genotyped in 1727 members of the third project of the Electricity Generating Authority of Thailand 3/1 cohort investigation. Each SNP was tested under three genetic effects (dominant, recessive and additive models) concerning the levels of total serum 25(OH)D [the sum of 25(OH)D2+3 and 3-epi-25(OH)D2+3], non-C3-epimers [25(OH)D2+3] and C3-epimers [3-epi-25(OH)D2+3], using linear regression analysis. Results:Among the participants, the median (range) levels of non-C3-epimers and C3-epimers were 22.7 (6.4-49.2)?ng/mL and 1.3 (0.01-14.2)?ng/mL, respectively. In regression analysis, we found the genetic variation of two SNPs, the DHCR7/NADSYN1 (rs12785878; G?>?T) and GC (rs2282679; T?>?G) under additive genetic models, explained the variation of C3-epimer levels about 1.5% (p?=?1.66?×?10-7) and 1.1% (p?=?1.10?×?10-5), respectively. Interestingly, participants carrying the minor T-allele of rs12785878 exhibited a trend to increase C3-epimer levels, while those carrying the minor G-allele of rs2282679 exhibited a trend to decrease levels of both non-C3-epimers and C3-epimers. In addition, CYP2R1 (rs2060793; G?>?A) was clearly associated only with non-C3-epimer levels (p?=?2.46?×?10-8). In multivariate analyses, sex, age and BMI were predictors for variation in C3-epimer concentration; sex and age for variation in non-C3-epimers. Conclusion:To the best of our knowledge, this is the first study to demonstrate genetic models concerning the variation in C3-epimer levels. Our results emphasize that genetic determinants and the potential factors of C3-epimers differ from non-C3-epimers. This study contributes fundamental knowledge of the endogenous vitamin D pathway.

SUBMITTER: Torugsa S

PROVIDER: S-EPMC5992311 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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The genetic determinants of circulating C3-epimers of 25-hydroxyvitamin D.

Torugsa Sirikunya S Nimitphong Hataikarn H Warodomwichit Daruneewan D Chailurkit La-Or LO Srijaruskul Kriangsuk K Chanprasertyothin Suwannee S Ongphiphadhanakul Boonsong B

Journal of clinical & translational endocrinology 20180422

<h4>Background</h4>The complexity of vitamin D metabolites especially the contribution of C3-epimers of 25-hydroxyvitamin D (C3-epimers) in human sera remains unclear. We hypothesized that genetic polymorphisms in the vitamin D-related gene pathway contribute to variation in C3-epimer levels. Therefore, we investigated candidate single nucleotide polymorphisms (SNPs) concerning C3-epimer levels.<h4>Methods</h4>The candidate SNPs, including <i>DHCR7/NADSYN1</i> (rs12785878), <i>CYP2R1</i> (rs2060 ...[more]

PMID: 29892565

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Project description:BackgroundLow serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival.MethodsSix genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer.ResultsThe 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; P heterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, P heterogeneity = 0.02).ConclusionsOur results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue.ImpactFurther studies are warranted to investigate the association in specific subgroups.

Project description:Background: Vitamin D may have anticancer activities. The high prevalence of vitamin D deficiency in African Americans (AAs) may be a contributing factor to the cancer health disparities between AAs and European Americans (EAs).Objectives: We compared concentrations of 25(OH)D and vitamin D-binding protein (VDBP) in AA and EA women and investigated determinants of the vitamin D-biomarker concentrations in both populations.Design: We used data and biospecimens from 909 AA and 847 EA healthy control subjects from the Carolina Breast Cancer Study (CBCS) and the Women's Circle of Health Study (WCHS) in the African American Breast Cancer Epidemiology and Risk Consortium. We measured plasma 25(OH)D and VDBP concentrations in all participants and genotyped 67 vitamin D-related genes in AA women only.Results: AA women had lower 25(OH)D concentrations than did EA women (mean ± SD: 14.2 ± 8.1 compared with 21.1 ± 11.5 ng/mL, respectively; P < 0.0001) but similar concentrations of VDBP (mean ± SD: 344 ± 133 compared with 336 ± 124 ?g/mL, respectively; P = 0.25). With VDBP and other factors controlled for, the observed racial difference in 25(OH)D concentrations did not diminish. Relations of demographic and lifestyle factors with 25(OH)D were similar between AA and EA women. Although none of the genetic variants that have been identified in previous genome-wide association studies of 25(OH)D concentrations in EAs were significant (P > 0.05) in AAs, AA women who carried the allele of a functional single nucleotide polymorphism rs4988235, which has been previously associated with lactase expression and lactose tolerance, had higher dietary vitamin D intake and higher measured 25(OH)D concentrations.Conclusions: AA women have lower concentrations of total 25(OH)D than EA women do, but both groups have similar VDBP concentrations, suggesting that there are lower concentrations of free 25(OH)D in AAs. Although demographic and lifestyle determinants of 25(OH)D concentrations are similar between the 2 groups, genetic determinants may be ethnicity specific. Larger studies in AAs will be needed to fully elucidate the underlying determinants of low vitamin D concentrations in AA populations.

Dataset Information

The genetic determinants of circulating C3-epimers of 25-hydroxyvitamin D.

Publications

The genetic determinants of circulating C3-epimers of 25-hydroxyvitamin D.

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