C-3 Epimer of 25-Hydroxyvitamin D : genetic variation and the effect on glycemic outcomes

• Main Author: Sirikunya Torugsa
• Other Authors: Boonsong Ongphiphadhanakul
• Language: English
• Published: Mahidol University. Mahidol University Library and Knowledge Center 2023
• Subjects: Diabetes; Glucose; Vitamin D.
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/89825
• Institution: Mahidol University

The difference in the forms of C3-epimer and basic metabolites may disturb the interpretation between vitamin D and glucose homeostasis. Therefore, this study aims to investigate causal relationship between non-C3-epimeric and C3-epimeric forms and glycemic outcomes by using both the Mendelian randomization (MR) analysis and a randomized controlled clinical trial (RCT) to obtain concrete results. The data and specimen sources were based on two projects. With regard to MR approach, they came from 1,727 participants in the third project of Electricity Generating Authority of Thailand (EGAT3/1) cohort. The other data and specimens came from a total of 79 prediabetic participants who were randomly assigned to receive vitamin D3 supplementation (VD group: dose 15,000 IU/weekly; n=45) or control groups (ND group: did not receive vitamin D3; n=34) during 12 month-follow-up period were used in a part of RCT. After being tested by MR analysis, the results indicated that based on additive effects: 1.) each copy of the minor T allele in the DHCR7/NADSYN1 (rs12785878) gene significantly increased in Ln(C3-epimer), 2.) each copy of the minor A allele in the CYP2R1 (rs2060793) gene significantly increased in Ln(non-C3-epimer), and 3.) each copy of the minor G allele in the GC (rs2282679) gene resulting in significantly decreased Ln(non-C3-epimer), and would be resulting significantly in the decreased in Ln(C3-epimer). All of these models did not reveal the change in levels of non-C3- or C3-epimeric forms affected the variation on FPG. Hence, these can be interpreted that there is no casual pathway between serum non-C3-epimeric/ C3-epimeric forms of vitamin D and FPG concentrations. Moreover, as for RCT, non-C3-epimer and C3-epimer levels significantly increased in only among VD group. Using ANCOVA with Bonferroni adjustment, absolute changes in both non-C3-epimer and C3-epimer forms did not show any significant difference in the effect on improving FPG concentration, fasting insulin, HOMA-IR, HOMA-B and disposition index in pre-diabetic subjects. Interestingly, this research provided novel knowledge. First of all, the rs12785878 in DHCR7/NADSYN1 was a strong association with only Ln(C3-epimer) (variant G>T, F = 27.625; P=1.66 x 10-7). These provided the possible genetic explanation for C3-epimeric form of vitamin D3 made by the process in the skin. Secondly, rs2060793 in the CYP2R1 gene polymorphism (variant G>A) was found strongly associated only with Ln(non-C3-epimer) (F = 31.383; P = 2.4612 x 10-8) by fitting in additive genetic model. This interpreted that the enzyme responsible for C3-epimerization differs from the nature vitamin D metabolic pathway. Finally, The SNP on GC gene, rs2282679 polymorphism demonstrated strong association with Ln(non-C3-epimer) (F = 85.297; P = 7.3012 x 10-20), and Ln(C3-epimer) (F = 19.429; P = 1.10 x 10-5). Both forms of vitamin D metabolites decreased progressively with the presence of the minor G allele (risk allele). This indicated that the polymorphism on GC gene (rs2282679) have more influence on the increased risk of vitamin D deficiency. In conclusion, in addressing the causality, MR strategy and RCT analysis have confirmed that there are no causal links between vitamin D metabolites and glycemic outcomes.