Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study

Observational studies have reported that Vitamin D deficiency and the risk type 2 diabetes are associated, but the causation is unclear. Mendelian randomization (MR) involving genetic variants as instrument variables (IVs) overcomes the reverse-casualty and unmeasured confounding. However, with limited sample size and IVs, previous MR studies showed inconsistent results. Leveraging by a largely increased sample size for both stages, we aim to provide an updated and precise estimate for the causality between Vitamin D and type 2 diabetes. A 2-sample multi-IVs MR was performed. IVs for circulating 25-hydroxyvitamin D (25(OH)D) were obtained from a genome-wide association study from UK biobank involving 329,247 subjects of European ancestry. The causal effect of 25(OH)D and type 2 diabetes was estimated using traditional inverse variance weighting and MR pleiotropy residual sum and outlier (MR-PRESSO) framework which provides a robust estimate by systematically filtering out IVs identified with potential pleiotropy effects. A higher genetically instrumented 25(OH)D was causally linked to reduced risk of type 2 diabetes risk by MR-PRESSO [odds ratio (OR) per standard deviation (SD) = 0.950, 95% confidence interval (CI) = 0.913–0.988, P = .010] after removing 13 (13/193) invalid IVs. In addition, we confirmed the causal role Vitamin D using 2 synthesis-related single-nucleotide polymorphisms (SNPs) which are consistent with previous MR studies [OR per SD = 0.894, 95% CI = 0.816–0.979, P = .016]. With a largely improved sample size, our results confirmed that genetically increased 25(OH)D concentration reduced the risk of type 2 diabetes and provided a more precise estimate for the effect size. The updated result empowers the role of Vitamin D and provides nontrivial evidence for interventional studies.