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

Diabetes Care. 2019 Dec;42(12):2197-2203. doi: 10.2337/dc19-1247. Epub 2019 Sep 23.


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 were used for supplementary analyses.

Results: Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For 1 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 1 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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Calcium / blood*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Humans
  • Male
  • Mendelian Randomization Analysis
  • Odds Ratio
  • Parathyroid Hormone / blood*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood


  • Parathyroid Hormone
  • Vitamin D
  • 25-hydroxyvitamin D
  • Calcium