The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
Creators: name: Zheng, Ju-Sheng
name: Luan, Jian’an
name: Sofianopoulou, Eleni
name: Sharp, Stephen J.
name: Day, Felix R.
name: Imamura, Fumiaki
name: Gundersen, Thomas E.
name: Lotta, Luca A.
name: Sluijs, Ivonne
name: Stewart, Isobel D.
name: Shah, Rupal L.
name: Van Der Schouw, Yvonne T.
name: Wheeler, Eleanor
name: Ardanaz, Eva
name: Boeing, Heiner
name: Dorronsoro, Miren
name: Dahm, Christina C.
name: Dimou, Niki
name: El-Fatouhi, Douae
name: Franks, Paul W.
name: Fagherazzi, Guy
name: Grioni, Sara
name: Huerta, José María
name: Heath, Alicia K.
name: Hansen, Louise
name: Jenab, Mazda
name: Jakszyn, Paula
name: Kaaks, Rudolf
name: Kühn, Tilman
name: Khaw, Kay-Tee
name: Laouali, Nasser
name: Masala, Giovanna
name: Nilsson, Peter M.
name: Overvad, Kim
name: Olsen, Anja
name: Panico, Salvatore
name: Quirós, J. Ramón
name: Rolandsson, Olov
name: Rodríguez-Barranco, Miguel
name: Sacerdote, Carlotta
name: Spijkerman, Annemieke M. W.
name: Tong, Tammy Y. N.
name: Tumino, Rosario
name: Tsilidis, Konstantinos K.
name: Danesh, John
name: Riboli, Elio
name: Butterworth, Adam S.
name: Langenberg, Claudia
name: Forouhi, Nita G.
name: Wareham, Nicholas J.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: subject: Research Article
subject: Medicine and health sciences
subject: Biology and life sciences
subject: Physical sciences
subject: FOS: Physical sciences
subject: FOS: Physical sciences
subject: Research and analysis methods

description: Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014
description: Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p &lt; 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p &lt; 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.