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

Abstract

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 HbA1c; 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 × 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.

Funding: UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.

Figure 1

Study design and mendelian randomisation analysis of SNPs associated with 25(OH)D concentrations and risk of type 2 diabetes Because of some missing genotyping data for each single nucleotide polymorphism (SNP), the sample sizes for each study varies; total sample sizes are shown. CCCS=Cambridgeshire case-control study. *Excludes data from EPIC-Norfolk already included in EPIC-InterAct.

Figure 2

Associations of SNPs related to vitamin D metabolism with circulating concentrations of 25(OH)D (A) and risk of type 2 diabetes (B) For analysis of 25-hydroxyvitamin D (25[OH]D), summary estimates were obtained from adults without diabetes from two studies, Ely and EPIC-Norfolk. For analysis of type 2 diabetes, summary estimates were obtained from four case-control studies (Cambridgeshire, ADDITION-Ely,, Norfolk Diabetes, and DIAGRAM¹⁸) and one case-cohort study (EPIC-InterAct¹⁷). SNPs=single nucleotide polymorphisms.

Figure 3

Mendelian randomisation and observational estimates for effect of a 1 SD reduction in 25(OH)D concentration on risk of type 2 diabetes The mendelian randomisation estimate (odds ratio [OR] with 95% CIs) was determined by instrumental variable analysis and the observational estimate (relative risk [RR] with 95% CIs) was determined by meta-analysis of prospective observational studies. 1 SD of 25-hydroxyvitamin D (25[OH]D) concentration was 25·0 nmol/L.

Figure 4

Meta-analysis of 22 prospective studies for associations of 1 SD lower 25(OH)D concentration with risk of type 2 diabetes in populations of European descent 1 SD of 25-hydroxyvitamin D (25[OH]D) concentration was 25·0 nmol/L. *Indicates studies added in this updated analysis (references 17–27 in appendix); other studies were included in our previous meta-analysis.