Torugsa Sirikunya, Nimitphong Hataikarn, Warodomwichit Daruneewan, Chailurkit La-Or, Srijaruskul Kriangsuk, Chanprasertyothin Suwannee, Ongphiphadhanakul Boonsong
Faculty of Medicine Ramathibodi Hospital and Institute of Nutrition, Mahidol University, 270 Rama 6th Road, Ratchathewi, Bangkok 10400, Thailand.
Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
J Clin Transl Endocrinol. 2018 Apr 22;12:36-41. doi: 10.1016/j.jcte.2018.04.002. eCollection 2018 Jun.
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.
The candidate SNPs, including (rs12785878), (rs2060793) and (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)D and 3-epi-25(OH)D], non-C3-epimers [25(OH)D] and C3-epimers [3-epi-25(OH)D], using linear regression analysis.
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 (rs12785878; G > T) and (rs2282679; T > G) under additive genetic models, explained the variation of C3-epimer levels about 1.5% ( = 1.66 × 10) and 1.1% ( = 1.10 × 10), 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, (rs2060793; G > A) was clearly associated only with non-C3-epimer levels ( = 2.46 × 10). In multivariate analyses, sex, age and BMI were predictors for variation in C3-epimer concentration; sex and age for variation in non-C3-epimers.
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.
维生素D代谢产物的复杂性，尤其是25-羟基维生素D的C3-差向异构体（C3-差向异构体）在人血清中的作用仍不清楚。我们推测维生素D相关基因途径中的基因多态性导致C3-差向异构体水平的差异。因此，我们研究了与C3-差向异构体水平相关的候选单核苷酸多态性（SNP）。
在泰国发电管理局第三项目3/1队列研究的1727名成员中，对包括（rs12785878）、（rs2060793）和（rs2282679）在内的候选SNP进行基因分型。使用线性回归分析，在三种遗传效应（显性、隐性和加性模型）下，对每个SNP就总血清25(OH)D[25(OH)D和3-表-25(OH)D的总和]、非C3-差向异构体[25(OH)D]和C3-差向异构体[3-表-25(OH)D]的水平进行检测。
在参与者中，非C3-差向异构体和C3-差向异构体的中位数（范围）水平分别为22.7（6.4 - 49.2）ng/mL和1.3（0.01 - 14.2）ng/mL。在回归分析中，我们发现两个SNP的基因变异，即加性遗传模型下的（rs12785878；G>T）和（rs2282679；T>G），分别解释了C3-差向异构体水平变异的约1.5%（=1.66×10）和1.1%（=1.10×10）。有趣的是，携带rs12785878次要T等位基因的参与者表现出C3-差向异构体水平升高的趋势，而携带rs2282679次要G等位基因的参与者表现出非C3-差向异构体和C3-差向异构体水平均降低的趋势。此外，（rs2060793；G>A）仅与非C3-差向异构体水平明显相关（=2.46×10）。在多变量分析中，性别、年龄和BMI是C3-差向异构体浓度变异的预测因素；性别和年龄是非C3-差向异构体变异的预测因素。
据我们所知，这是第一项证明与C3-差向异构体水平变异相关的遗传模型的研究。我们的结果强调，C3-差向异构体的遗传决定因素和潜在因素与非C3-差向异构体不同。本研究为内源性维生素D途径提供了基础知识。
