PLoS Medicine (Oct 2020)

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

  • Ju-Sheng Zheng,
  • Jian'an Luan,
  • Eleni Sofianopoulou,
  • Stephen J Sharp,
  • Felix R Day,
  • Fumiaki Imamura,
  • Thomas E Gundersen,
  • Luca A Lotta,
  • Ivonne Sluijs,
  • Isobel D Stewart,
  • Rupal L Shah,
  • Yvonne T van der Schouw,
  • Eleanor Wheeler,
  • Eva Ardanaz,
  • Heiner Boeing,
  • Miren Dorronsoro,
  • Christina C Dahm,
  • Niki Dimou,
  • Douae El-Fatouhi,
  • Paul W Franks,
  • Guy Fagherazzi,
  • Sara Grioni,
  • José María Huerta,
  • Alicia K Heath,
  • Louise Hansen,
  • Mazda Jenab,
  • Paula Jakszyn,
  • Rudolf Kaaks,
  • Tilman Kühn,
  • Kay-Tee Khaw,
  • Nasser Laouali,
  • Giovanna Masala,
  • Peter M Nilsson,
  • Kim Overvad,
  • Anja Olsen,
  • Salvatore Panico,
  • J Ramón Quirós,
  • Olov Rolandsson,
  • Miguel Rodríguez-Barranco,
  • Carlotta Sacerdote,
  • Annemieke M W Spijkerman,
  • Tammy Y N Tong,
  • Rosario Tumino,
  • Konstantinos K Tsilidis,
  • John Danesh,
  • Elio Riboli,
  • Adam S Butterworth,
  • Claudia Langenberg,
  • Nita G Forouhi,
  • Nicholas J Wareham

DOI
https://doi.org/10.1371/journal.pmed.1003394
Journal volume & issue
Vol. 17, no. 10
p. e1003394

Abstract

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BackgroundPrior 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 findingsWe 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 ConclusionsOur 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.