Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study

Background Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach. Methods Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH) D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH) D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA(1c); 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH) D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH) D concentration and type 2 diabetes. Findings All four SNPs were associated with 25(OH) D concentrations (p<10(-6)). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1.01 (95% CI 0.75-1.36; p = 0.94) per 25.0 nmol/L (1 SD) lower 25(OH) D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1.21 (1.16-1.27; p = 7.3 x 10(-19)). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p > 0.25). Interpretation The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH D concentration and also reduce the risk of type 2 diabetes. Copyright (C) Ye et al. Open Access article distributed under the terms of CC BY.