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

Sirikunya Torugsa; Hataikarn Nimitphong; Daruneewan Warodomwichit; La-Or Chailurkit; Kriangsuk Srijaruskul; Suwannee Chanprasertyothin; Boonsong Ongphiphadhanakul

doi:10.1016/j.jcte.2018.04.002

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

J Clin Transl Endocrinol. 2018 Apr 22:12:36-41. doi: 10.1016/j.jcte.2018.04.002. eCollection 2018 Jun.

Authors

Sirikunya Torugsa¹, Hataikarn Nimitphong², Daruneewan Warodomwichit³, La-Or Chailurkit², Kriangsuk Srijaruskul², Suwannee Chanprasertyothin⁴, Boonsong Ongphiphadhanakul²

Affiliations

¹ Faculty of Medicine Ramathibodi Hospital and Institute of Nutrition, Mahidol University, 270 Rama 6th Road, Ratchathewi, Bangkok 10400, Thailand.
² Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³ Division of Nutrition and Biochemical Medicine, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
⁴ Research Center, Ramathibodi Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand.

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.

Keywords: C3-epimer; CYP2R1; DHCR7/NADSYN1; GC; Vitamin D.