Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Ye, Zheng; Sharp, Stephen J; Burgess, Stephen; Scott, Robert A; Imamura, Fumiaki; Langenberg, Claudia; Wareham, Nicholas J; Forouhi, Nita G; InterAct Consortium
• Is Part Of: Lancet. Volume 3:Issue 1(2015)
• Page Start: 35
• Page End: 42
• Publication Date: 2015-01
• Subjects: Diabetes -- Periodicals; Endocrinology -- Periodicals; Endocrine glands -- Diseases -- Periodicals; 616.4
• DOI: 10.1016/S2213-8587(14)70184-6
• Languages: English
• ISSNs: 2213-8587

Abstract

<abstract abstract-type="author" id="ceab10"> <title id="cestitle10">Summary</title> <sec> <title id="cestitle20">Background</title> <p id="spara120">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.</p> </sec> <sec> <title id="cestitle30">Methods</title> <p id="spara130">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: <italic>DHCR7</italic> (related to vitamin D synthesis), <italic>CYP2R1</italic> (hepatic 25-hydroxylation), <italic>DBP</italic> (also known as <italic>GC</italic>; transport), and <italic>CYP24A1</italic> (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<sub>1c</sub>; 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.</p> </sec> <sec> <title id="cestitle40">Findings</title> <p id="spara140">All four SNPs were associated with 25(OH)D concentrations (p<10<sup>−6</sup>). 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<sup>−19</sup>). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0·25).</p> </sec> <sec> <title id="cestitle50">Interpretation</title> <p id="spara150">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.</p> </sec> <sec> <title id="cestitle60">Funding</title> <p id="spara160">UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.</p> </sec> </abstract>