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

Autoři: Ju-Sheng Zheng aff001;  Jian’an Luan aff001;  Eleni Sofianopoulou aff003;  Stephen J. Sharp aff001;  Felix R. Day aff001;  Fumiaki Imamura aff001;  Thomas E. Gundersen aff005;  Luca A. Lotta aff001;  Ivonne Sluijs aff006;  Isobel D. Stewart aff001;  Rupal L. Shah aff001;  Yvonne T. van der Schouw aff006;  Eleanor Wheeler aff001;  Eva Ardanaz aff007;  Heiner Boeing aff010;  Miren Dorronsoro aff011;  Christina C. Dahm aff012;  Niki Dimou aff013;  Douae El-Fatouhi aff014;  Paul W. Franks aff015;  Guy Fagherazzi aff014;  Sara Grioni aff017;  José María Huerta aff009;  Alicia K. Heath aff019;  Louise Hansen aff020;  Mazda Jenab aff013;  Paula Jakszyn aff021;  Rudolf Kaaks aff023;  Tilman Kühn aff023;  Kay-Tee Khaw aff024;  Nasser Laouali aff014;  Giovanna Masala aff025;  Peter M. Nilsson aff015;  Kim Overvad aff012;  Anja Olsen aff020;  Salvatore Panico aff027;  J. Ramón Quirós aff028;  Olov Rolandsson aff029;  Miguel Rodríguez-Barranco aff009;  Carlotta Sacerdote aff032;  Annemieke M. W. Spijkerman aff033;  Tammy Y. N. Tong aff034;  Rosario Tumino aff035;  Konstantinos K. Tsilidis aff019;  John Danesh aff003;  Elio Riboli aff019;  Adam S. Butterworth aff003;  Claudia Langenberg aff001;  Nita G. Forouhi aff001;  Nicholas J. Wareham aff001
Působiště autorů: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom aff001;  Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China aff002;  MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom aff003;  National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom aff004;  VITAS, Oslo, Norway aff005;  Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands aff006;  Navarra Public Health Institute, Pamplona, Spain aff007;  Navarra Institute for Health Research (IdiSNA), Pamplona, Spain aff008;  CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain aff009;  Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany aff010;  Public Health Division of Gipuzkoa, San Sebastian, Spain aff011;  Department of Public Health, Aarhus University, Aarhus, Denmark aff012;  International Agency for Research on Cancer, Lyon, France aff013;  Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris South–Paris Saclay University, Villejuif, France aff014;  Department of Clinical Sciences, Lund University, Malmö, Sweden aff015;  Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg aff016;  Epidemiology and Prevention Unit, Milan, Italy aff017;  Department of Epidemiology, Murcia Regional Health Council, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain aff018;  Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom aff019;  Danish Cancer Society Research Center, Copenhagen, Denmark aff020;  Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology–Institut d’Investigació Biomédica de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain aff021;  Facultat Ciències Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain aff022;  Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany aff023;  Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom aff024;  Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy aff025;  Department of Cardiology, Aalborg University Hospital, Aarhus, Denmark aff026;  Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy aff027;  Public Health Directorate, Asturias, Spain aff028;  Family Medicine Division, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden aff029;  Andalusian School of Public Health (EASP), Granada, Spain aff030;  Instituto de Investigación Biosanitaria de Granada, Universidad de Granada, Granada, Spain aff031;  Unit of Cancer Epidemiology, Città della Salute e della Scienza di Torino University Hospital–University of Turin and Center for Cancer Prevention (CPO), Torino, Italy aff032;  National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands aff033;  Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom aff034;  Azienda Sanitaria Provinciale, Ragusa, Italy aff035;  Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece aff036;  British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom aff037;  Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom aff038
Vyšlo v časopise: The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis. PLoS Med 17(10): e32767. doi:10.1371/journal.pmed.1003394
Kategorie: Research Article



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.


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.

Klíčová slova:

Genetic loci – Genetics – Genome-wide association studies – Metaanalysis – Metabolites – Single nucleotide polymorphisms – Type 2 diabetes – vitamín D


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