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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Ju-Sheng Zheng, University of Cambridge, Westlake University, Storbritannien
  • Jian'an Luan, University of Cambridge, Storbritannien
  • Eleni Sofianopoulou, University of Cambridge, Storbritannien
  • Stephen J Sharp, University of Cambridge, Storbritannien
  • Felix R Day, University of Cambridge, Storbritannien
  • Fumiaki Imamura, University of Cambridge, Storbritannien
  • Thomas E Gundersen, Vitas AS, Oslo, Norway., Norge
  • Luca A Lotta, University of Cambridge, Storbritannien
  • Ivonne Sluijs, Utrecht University, Utrecht, Holland
  • Isobel D Stewart, University of Cambridge, Storbritannien
  • Rupal L Shah, University of Cambridge, Storbritannien
  • Yvonne T van der Schouw, Utrecht University, Utrecht, Holland
  • Eleanor Wheeler, University of Cambridge, Storbritannien
  • Eva Ardanaz, Navarra Public Health Institute, Navarra Institute for Health Research (IdiSNA), 31003 Pamplona, Spain., CIBERESP, Consortium for Biomedical Research in Epidemiology and Public Health, Spanien
  • Heiner Boeing, German Institute of Human Nutrition Potsdam-Rehbruecke, Potsdam, Germany., Tyskland
  • Miren Dorronsoro, Public Health Division of Gipuzkoa, San Sebastian, Spain., Spanien
  • Christina C Dahm
  • Niki Dimou, IARC, Frankrig
  • Douae El-Fatouhi, CESP UMR1018, INSERM, Institut Gustave Roussy, Paris South University-Paris-Saclay University, Villejuif, France., Frankrig
  • Paul W Franks, Lund University, Malmö, Sverige
  • Guy Fagherazzi, CESP UMR1018, INSERM, Institut Gustave Roussy, Paris South University-Paris-Saclay University, Villejuif, France., Population Health Department, Luxembourg Institute of Health, Strassen, Luxembourg., Frankrig
  • Sara Grioni, Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Italien
  • José María Huerta, CIBERESP, Consortium for Biomedical Research in Epidemiology and Public Health, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spanien
  • Alicia K Heath, Imperial College, Storbritannien
  • Louise Hansen, Danish Cancer Society Research Center, The Danish Cancer Society, Copenhagen, Danmark
  • Mazda Jenab, IARC, Frankrig
  • Paula Jakszyn, Catalan Institute of Oncology-Institut d'Investigació Biomédica de Bellvitge, Facultat de Ciències de la Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain., Spanien
  • Rudolf Kaaks, German Cancer Research Center (DKFZ), Tyskland
  • Tilman Kühn, German Cancer Research Center (DKFZ), Tyskland
  • Kay-Tee Khaw, University of Cambridge, Storbritannien
  • Nasser Laouali, CESP UMR1018, INSERM, Institut Gustave Roussy, Paris South University-Paris-Saclay University, Villejuif, France., Frankrig
  • Giovanna Masala, Institute for Cancer Research, Italien
  • Peter M Nilsson, Lund University, Malmö, Sverige
  • Kim Overvad
  • Anja Olsen
  • Salvatore Panico, University of Naples, Italien
  • J Ramón Quirós, Public Health Directorate, Asturias, Spain., Spanien
  • Olov Rolandsson, University of Umeå, Umeå, Sweden., Sverige
  • Miguel Rodríguez-Barranco, Andalusian School of Public Health (EASP), Granada, CIBERESP, Consortium for Biomedical Research in Epidemiology and Public Health, Universidad de Granada, Spanien
  • Carlotta Sacerdote, Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, ItalyHuman Genetics Foundation (HuGeF), Torino, Italy., Italien
  • Annemieke M W Spijkerman, National Institute for Public Health and the Environment (RIVM), Holland
  • Tammy Y N Tong, University of Oxford, Oxford, Storbritannien
  • Rosario Tumino, Azienda Sanitaria Provinciale di Ragusa, Italien
  • Konstantinos K Tsilidis, Imperial College, University of Ioannina School of Medicine, Storbritannien
  • John Danesh, University of Cambridge, British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Storbritannien
  • Elio Riboli, Imperial College, Storbritannien
  • Adam S Butterworth, University of Cambridge, Storbritannien
  • Claudia Langenberg, University of Cambridge, Storbritannien
  • Nita G Forouhi, University of Cambridge, Storbritannien
  • Nicholas J Wareham, University of Cambridge, Storbritannien

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 < 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 < 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.

OriginalsprogEngelsk
Artikelnummere1003394
TidsskriftPLOS Medicine
Vol/bind17
Nummer10
Antal sider21
ISSN1549-1277
DOI
StatusUdgivet - okt. 2020

Se relationer på Aarhus Universitet Citationsformater

ID: 199192089