Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Type 2 Diabetes: A Prospective Cohort Study

Context: Vitamin D status has been associated with risk of type 2 diabetes (T2D), but evidence is scarce regarding whether such relation differs by glycemic status. Objective: To prospectively investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and risk of incident T2D across the glycemic spectrum and the modification effect of genetic variants in the vitamin D receptor (VDR). Methods: This prospective study included 379 699 participants without T2D at baseline from the UK Biobank. Analyses were performed according to glycemic status and HbA1c levels. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs. Results: During a median of 14.1 years of follow-up, 6315 participants with normoglycemia and 9085 patients with prediabetes developed T2D. Compared with individuals with 25(OH)D < 25 nmol/L, the multivariable-adjusted HRs (95% CIs) of incident T2D for those with 25(OH)D >= 75 nmol/L was 0.62 (0.56, 0.70) among the normoglycemia group and 0.64 (0.58, 0.70) among the prediabetes group. A significant interaction was observed between 25(OH)D and VDR polymorphisms among participants with prediabetes (P interaction = .017), whereby the reduced HR of T2D associated with higher 25(OH)D was more prominent in those carrying the T allele of rs1544410. Triglyceride levels mediated 26% and 34% of the association between serum 25(OH)D and incident T2D among participants with normoglycemia and prediabetes, respectively. Conclusion: Higher serum 25(OH)D concentrations were associated with lower T2D risk across the glycemic spectrum below the threshold for diabetes, and the relations in prediabetes were modified by VDR polymorphisms. Improving the lipid profile, mainly triglycerides, accounted for part of the favorable associations.