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

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

Author information

1
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
2
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Unit of Translational Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
4
Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston, MA.
5
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden susanna.larsson@surgsci.uu.se.

Abstract

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.

PMID:
31548248
DOI:
10.2337/dc19-1247

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