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The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.
PLoS Med. 2020 10; 17(10):e1003394.PM

Abstract

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.

Authors+Show Affiliations

MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom. 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.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 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.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.VITAS, Oslo, Norway.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.Navarra Public Health Institute, Pamplona, Spain. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.Public Health Division of Gipuzkoa, San Sebastian, Spain.Department of Public Health, Aarhus University, Aarhus, Denmark.International Agency for Research on Cancer, Lyon, France.Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris South-Paris Saclay University, Villejuif, France.Department of Clinical Sciences, Lund University, Malmö, Sweden.Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris South-Paris Saclay University, Villejuif, France. Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg.Epidemiology and Prevention Unit, Milan, Italy.CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain. Department of Epidemiology, Murcia Regional Health Council, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, Murcia, Spain.Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.Danish Cancer Society Research Center, Copenhagen, Denmark.International Agency for Research on Cancer, Lyon, France.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. Facultat Ciències Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.Center of Research in Epidemiology and Population Health, UMR 1018 Inserm, Institut Gustave Roussy, Paris South-Paris Saclay University, Villejuif, France.Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.Department of Clinical Sciences, Lund University, Malmö, Sweden.Department of Public Health, Aarhus University, Aarhus, Denmark. Department of Cardiology, Aalborg University Hospital, Aarhus, Denmark.Danish Cancer Society Research Center, Copenhagen, Denmark.Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy.Public Health Directorate, Asturias, Spain.Family Medicine Division, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain. Andalusian School of Public Health (EASP), Granada, Spain. Instituto de Investigación Biosanitaria de Granada, Universidad de Granada, Granada, Spain.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.National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.Azienda Sanitaria Provinciale, Ragusa, Italy.Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 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. British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom. Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 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.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33064751

Citation

Zheng, Ju-Sheng, et al. "The Association Between Circulating 25-hydroxyvitamin D Metabolites and Type 2 Diabetes in European Populations: a Meta-analysis and Mendelian Randomisation Analysis." PLoS Medicine, vol. 17, no. 10, 2020, pp. e1003394.
Zheng JS, Luan J, Sofianopoulou E, et al. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis. PLoS Med. 2020;17(10):e1003394.
Zheng, J. S., Luan, J., Sofianopoulou, E., Sharp, S. J., Day, F. R., Imamura, F., Gundersen, T. E., Lotta, L. A., Sluijs, I., Stewart, I. D., Shah, R. L., van der Schouw, Y. T., Wheeler, E., Ardanaz, E., Boeing, H., Dorronsoro, M., Dahm, C. C., Dimou, N., El-Fatouhi, D., ... Wareham, N. J. (2020). The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis. PLoS Medicine, 17(10), e1003394. https://doi.org/10.1371/journal.pmed.1003394
Zheng JS, et al. The Association Between Circulating 25-hydroxyvitamin D Metabolites and Type 2 Diabetes in European Populations: a Meta-analysis and Mendelian Randomisation Analysis. PLoS Med. 2020;17(10):e1003394. PubMed PMID: 33064751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis. AU - Zheng,Ju-Sheng, AU - Luan,Jian'an, AU - Sofianopoulou,Eleni, AU - Sharp,Stephen J, AU - Day,Felix R, AU - Imamura,Fumiaki, AU - Gundersen,Thomas E, AU - Lotta,Luca A, AU - Sluijs,Ivonne, AU - Stewart,Isobel D, AU - Shah,Rupal L, AU - van der Schouw,Yvonne T, AU - Wheeler,Eleanor, AU - Ardanaz,Eva, AU - Boeing,Heiner, AU - Dorronsoro,Miren, AU - Dahm,Christina C, AU - Dimou,Niki, AU - El-Fatouhi,Douae, AU - Franks,Paul W, AU - Fagherazzi,Guy, AU - Grioni,Sara, AU - Huerta,José María, AU - Heath,Alicia K, AU - Hansen,Louise, AU - Jenab,Mazda, AU - Jakszyn,Paula, AU - Kaaks,Rudolf, AU - Kühn,Tilman, AU - Khaw,Kay-Tee, AU - Laouali,Nasser, AU - Masala,Giovanna, AU - Nilsson,Peter M, AU - Overvad,Kim, AU - Olsen,Anja, AU - Panico,Salvatore, AU - Quirós,J Ramón, AU - Rolandsson,Olov, AU - Rodríguez-Barranco,Miguel, AU - Sacerdote,Carlotta, AU - Spijkerman,Annemieke M W, AU - Tong,Tammy Y N, AU - Tumino,Rosario, AU - Tsilidis,Konstantinos K, AU - Danesh,John, AU - Riboli,Elio, AU - Butterworth,Adam S, AU - Langenberg,Claudia, AU - Forouhi,Nita G, AU - Wareham,Nicholas J, Y1 - 2020/10/16/ PY - 2019/09/12/received PY - 2020/09/11/accepted PY - 2020/10/16/entrez PY - 2020/10/17/pubmed PY - 2020/12/22/medline SP - e1003394 EP - e1003394 JF - PLoS medicine JO - PLoS Med VL - 17 IS - 10 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/33064751/The_association_between_circulating_25_hydroxyvitamin_D_metabolites_and_type_2_diabetes_in_European_populations:_A_meta_analysis_and_Mendelian_randomisation_analysis_ L2 - https://dx.plos.org/10.1371/journal.pmed.1003394 DB - PRIME DP - Unbound Medicine ER -