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

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

Ye Z ，Sharp SJ ，Burgess S ，Scott RA ，Imamura F ，InterAct Consortium ，Langenberg C ，Wareham NJ ，Forouhi NG ... -  《-》

Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults.

Lu L ，Bennett DA ，Millwood IY ，Parish S ，McCarthy MI ，Mahajan A ，Lin X ，Bragg F ，Guo Y ，Holmes MV ，Afzal S ，Nordestgaard BG ，Bian Z ，Hill M ，Walters RG ，Li L ，Chen Z ，Clarke R ... -  《-》

Association of serum 25-hydroxyvitamin D with metabolic syndrome and type 2 diabetes: a one sample Mendelian randomization study.

Xiao J ，Lv J ，Wang S ，Zhou Y ，Chen L ，Lu J ，Zhang X ，Wang X ，Gu Y ，Lu Q ... -  《BMC Geriatrics》

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

Zheng JS ，Luan J ，Sofianopoulou E ，Sharp SJ ，Day FR ，Imamura F ，Gundersen TE ，Lotta LA ，Sluijs I ，Stewart ID ，Shah RL ，van der Schouw YT ，Wheeler E ，Ardanaz E ，Boeing H ，Dorronsoro M ，Dahm CC ，Dimou N ，El-Fatouhi D ，Franks PW ，Fagherazzi G ，Grioni S ，Huerta JM ，Heath AK ，Hansen L ，Jenab M ，Jakszyn P ，Kaaks R ，Kühn T ，Khaw KT ，Laouali N ，Masala G ，Nilsson PM ，Overvad K ，Olsen A ，Panico S ，Quirós JR ，Rolandsson O ，Rodríguez-Barranco M ，Sacerdote C ，Spijkerman AMW ，Tong TYN ，Tumino R ，Tsilidis KK ，Danesh J ，Riboli E ，Butterworth AS ，Langenberg C ，Forouhi NG ，Wareham NJ ... -  《-》

Association of 25-hydroxyvitamin D with cardiometabolic risk factors and metabolic syndrome: a mendelian randomization study.

Chen C ，Chen Y ，Weng P ，Xia F ，Li Q ，Zhai H ，Wang N ，Lu Y ... -  《Nutrition Journal》