Genetic Prediction of Serum 25-Hydroxyvitamin D, Calcium, and Parathyroid Hormone Levels in Relation to Development of Type 2 Diabetes: A Mendelian Randomization Study

OBJECTIVE We conducted a Mendelian randomization study to investigate the associations of genetically predicted serum 25-hydroxyvitamin D (S-25OHD), calcium (S-Ca), and parathyroid hormone (S-PTH) levels with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Seven, six, and five single nucleotide polymorphisms (SNPs) associated with S-25OHD, S-Ca, and S-PTH levels, respectively, were used as instrumental variables. Data on T2DM were available for 74,124 case subjects with T2DM and 824,006 control subjects. The inverse variance–weighted method was used for the primary analyses, and the weighted median and Mendelian randomization (MR)–Egger methods as supplementary analyses. RESULTS Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For one SD increment of S-25OHD levels, the odds ratio (OR) of T2DM was 0.94 (95% CI 0.88–0.99; P = 0.029) in an analysis based on all seven SNPs and 0.90 (95% CI 0.83–0.98; P = 0.011) in an analysis based on three SNPs within or near genes involved in vitamin D synthesis. Only the association based on the SNPs involved in vitamin D synthesis remained in the weighted median analysis and no pleiotropy was detected (P = 0.153). Pleiotropy was detected in the analysis of S-Ca (P = 0.013). After correcting for this bias using MR-Egger regression, the OR of T2DM per one-SD increment of S-Ca levels was 1.41 (95% CI 1.12–1.77; P = 0.003). CONCLUSIONS Modest lifelong higher S-25OHD levels were associated with reduced odds of T2DM, but the association was only robust for SNPs in the vitamin D synthesis pathway. The possible role of S-Ca levels for T2DM development requires further research.