Associations between genetic variants of vitamin D metabolic pathway and gestational diabetes mellitus: the potential mediation role of serum 25(OH)D₃

Background: Circulating vitamin D concentrations have been recognized as a risk factor for GDM. The pathway genes of vitamin D synthesis and metabolism have been shown to be strongly associated with serum vitamin D. This study aimed to evaluate the association between genetic variations and GDM risk, and to further explore the potential mediating role of serum 25(OH)D₃ in these relationships. Methods: A nested case-control study including 131 cases of GDM and 131 controls from the Zhengzhou Birth Cohort established since 2021. We genotyped nine SNPs using the TaqMan probe method and measured serum 25(OH)D₃ by ELISA. Results: The VDR rs731236-G allele was associated with reduced GDM risk: the OR (95% CI) was 0.56 (0.34, 0.93) in the multivariable adjusted model. Conversely, the VDR rs7975232-A allele was associated with a higher risk of GDM (OR: 1.56; 95% CI: 1.04, 2.33). Higher 25(OH)D₃ levels were inversely associated with GDM risk (OR: 0.36; 95% CI: 0.20, 0.67; P_trend <0.01). Each 1-unit increment of log-transformed 25(OH)D₃ level was associated with a 79% lower risk of GDM (OR 0.21, 95% CI: 0.09, 0.46). Mediation analyses indicated that 25(OH)D₃ explained 24.7% of the protective effect of the VDR rs731236 variant [Indirect effect= -0.06 (-0.12, -0.01)], and 29.6% of the detrimental effect of VDR rs7975232 and GDM risk [indirect effect = 0.07 (0.03, 0.13)]. Conclusions: The study suggested a significant association of VDR rs7975232 and rs731236 polymorphisms with GDM risk among the Chinese population. Higher 25(OH)D₃ levels were associated with a decreased risk of GDM. Additionally, circulating 25(OH)D₃ partially mediated the association between variant genotype of SNPs at VDR-rs731236 and VDR-rs7975232 and GDM risk, but the relatively wide CI prompted cautious interpretation. These findings emphasize the important role of genetic variants in VDR in the pathogenesis of GDM. Further studies with larger cohort sample sizes should be conducted to confirm the present findings. Clinical trial number: Not applicable.