Meta-analysis2020Industry fundedOpen access

Funded in part by AstraZeneca, Sanofi, Biogen, Regeneron Pharmaceuticals, Novo Nordisk

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

Zheng JS, Luan J, Sofianopoulou E, Sharp SJ, Day FR, Imamura F, Gundersen TE, Lotta LA, Sluijs I, Stewart ID, Shah RL, van der Schouw YT, Wheeler E, Ardanaz E, Boeing H, Dorronsoro M, Dahm CC, Dimou N, El-Fatouhi D, Franks PW, Fagherazzi G, Grioni S, Huerta JM, Heath AK, Hansen L, Jenab M, Jakszyn P, Kaaks R, Kühn T, Khaw KT, Laouali N, Masala G, Nilsson PM, Overvad K, Olsen A, Panico S, Quirós JR, Rolandsson O, Rodríguez-Barranco M, Sacerdote C, Spijkerman AMW, Tong TYN, Tumino R, Tsilidis KK, Danesh J, Riboli E, Butterworth AS, Langenberg C, Forouhi NG, Wareham NJ

PLoS medicine · 61 citations

Review labels

Author industry tiesIndustry funded

Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.

How it was studied

Design
Meta-analysis (indexed by PubMed)
Studied in
People
Main outcome
Clinical events such as disease or death

Who paid for it

Funding
Industry funded
Company
AstraZeneca
Company
Sanofi
Government
World Health Organization
Company
Biogen
Nonprofit
Compagnia di San Paolo
University or hospital
Deutsches Krebsforschungszentrum
University or hospital
Centre International de Recherche sur le Cancer
Company
Regeneron Pharmaceuticals
University or hospital
Westlake University
Nonprofit
Cancer Research UK
Government
National Institute for Health and Care Research
Nonprofit
British Heart Foundation
University or hospital
University of Cambridge
University or hospital
Imperial College London
Government
European Commission
Government
Bundesministerium für Bildung und Forschung
Government
Generalitat de Catalunya
University or hospital
Cambridge University Hospitals
Nonprofit
Hjärt-Lungfonden
Company
Novo Nordisk
Government
Vetenskapsrådet
Nonprofit
Deutsche Krebshilfe
Government
Medical Research Council
Nonprofit
World Cancer Research Fund
Government
Agència de Gestió d'Ajuts Universitaris i de Recerca
Government
Sixth Framework Programme
Government
NIHR Cambridge Biomedical Research Centre
Government
H2020 Marie Skłodowska-Curie Actions
Government
FP7 Health
Government
MRC Cambridge Initiative
Government
European Research Council
Government
National Institute for Health Research (NIHR)
Government
Medical Research Council Epidemiology Unit
University or hospital
NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme
Authors
At least one author declares a financial tie to industry
Grants
Medical Research Council (IS-BRC-1215-20014); Medical Research Council (MC_UU_12015/1); Medical Research Council (MC_UU_12015/5); Medical Research Council (M012190/1); Westlake University (YSYY0209); NIHR Cambridge Biomedical Research Centre ((BRC-1215-20014)); Bundesministerium für Bildung und Forschung (IS-BRC-1215-20014); European Commission (IS-BRC-1215-20014); Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR 726); Cancer Research UK (C570/ A16491); National Institute for Health and Care Research (C8221/A19170); British Heart Foundation (MR/L003120/1); World Cancer Research Fund (IS-BRC-1215-20014); Medical Research Council (C570/A16491); British Heart Foundation (RG/13/13/30194; RG/18/13/33946); H2020 Marie Skłodowska-Curie Actions (701708); World Cancer Research Fund (MR/M012190/1); British Heart Foundation (RG/18/13/33946); European Commission (LSHM_CT_2006_037197); Deutsche Krebshilfe (MR/M012190/1); Compagnia di San Paolo (MR/M012190/1); Compagnia di San Paolo (IS-BRC-1215-20014); Medical Research Council (MC_UU_12015/5); Deutsches Krebsforschungszentrum (C8221/A19170); World Cancer Research Fund (C8221/A19170); Medical Research Council (MC_UU_12015); National Institute for Health and Care Research ([IS-BRC-1215-20014); Bundesministerium für Bildung und Forschung (C8221/A19170); FP7 Health (HEALTH-F2-2012-279233); Sixth Framework Programme (LSHM_CT_2006_037197); Medical Research Council (MR/M012190); World Cancer Research Fund (C570/A16491); Deutsche Krebshilfe (IS-BRC-1215-20014); NIHR Cambridge Biomedical Research Centre (1215-20014); National Institute for Health and Care Research (BRC1215-20014); National Institute for Health and Care Research (C570/A16491); Bundesministerium für Bildung und Forschung (MR/M012190/1); Cancer Research UK (IS-BRC-1215-20014); NIHR Cambridge Biomedical Research Centre (MR/L003120/1); Vetenskapsrådet (IS-BRC-1215-20014); Medical Research Council (C8221/A19170); European Commission (C570/A16491); European Commission (C8221/A19170); Medical Research Council (MR/L003120/1); European Commission (HORIZON2020); Medical Research Council (MR/M012190/1); Deutsche Krebshilfe (C570/A16491); NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014); Centre International de Recherche sur le Cancer (MR/M012190/1); Medical Research Council (RG/18/13/33946); Cancer Research UK (BRC-1215-20014); European Commission (MR/M012190/1); Generalitat de Catalunya (2014 SGR 726); Medical Research Council (MC_UU_12015/2); Deutsche Krebshilfe (C8221/A19170); National Institute for Health and Care Research (MC_UU_12015/1); Vetenskapsrådet (BRC-1215-20014); University of Cambridge (BRC-1215-20014); NIHR Cambridge Biomedical Research Centre (BRC-1215); National Institute for Health and Care Research (IS-BRC-1215); Cancer Research UK (MR/M012190/1); European Commission (279233); Medical Research Council (BRC-1215-20014); Deutsches Krebsforschungszentrum (IS-BRC-1215-20014); Centre International de Recherche sur le Cancer (C570/A16491); National Institute for Health and Care Research (RG/18/13/33946); Cancer Research UK (C8221/A19170); Medical Research Council (MC_UU_12015/1); Cancer Research UK (A16491); European Commission (701708); Deutsches Krebsforschungszentrum (C570/A16491); British Heart Foundation (RG/13/13/30194); Agència de Gestió d'Ajuts Universitaris i de Recerca (MR/M012190/1); Cancer Research UK (A19170); Medical Research Council (MR/L003120); Deutsches Krebsforschungszentrum (MR/M012190/1); Bundesministerium für Bildung und Forschung (C570/A16491); Centre International de Recherche sur le Cancer (C8221/A19170); Vetenskapsrådet (C8221/A19170); British Heart Foundation (IS-BRC-1215-20014); National Institute for Health and Care Research (NF-SI-0617-10149); Cancer Research UK (30194); National Institute for Health and Care Research (MR/M012190/1); Vetenskapsrådet (C570/A16491); Vetenskapsrådet (MR/M012190/1); Cancer Research UK (MC-UU_12015/1); Medical Research Council (MR/L003120/1); Generalitat de Catalunya (2014SGR)

Based on 34 listed funder(s) and full-text disclosure statement.

Publication

Published
2020-10-16 · PLoS Med · vol. 17 · issue 10 · p. e1003394
Publisher
Public Library of Science
Cited
74 citations · more than 93% of similar papers · 2.9× the field average
Impact
Top 10% most cited in its field
References
43 works
Access
Open access (journal) · CC-BY
Research areas
Vitamin D Research Studies · Genetic Associations and Epidemiology · Nutrition, Genetics, and Disease
Keywords
Type 2 diabetes, Meta-analysis, Observational study, Vitamin D and neurology, Medicine, Genetic association, Confounding, European Prospective Investigation into Cancer and Nutrition, Internal medicine, Genome-wide association study, Mendelian randomization, Diabetes mellitus, Oncology, Genetics, Prospective cohort study, Biology, Endocrinology, Single-nucleotide polymorphism, Gene, Genotype, Genetic variants
MeSH
humans, diabetes mellitus, type 2, vitamin d, risk factors, prospective studies, dietary supplements, adult, middle aged, female, male, genome-wide association study, mendelian randomization analysis, white people
DOI ↗PubMed Central ↗OpenAlex ↗

50 authors

From GB, CN, NO, NL, ES, DE, DK, FR, SE, LU, IT, GR

  • Ju‐Sheng Zheng · correspondingUniversity of Cambridge; Westlake University; MRC Epidemiology Unit
  • Jian’an LuanUniversity of Cambridge; MRC Epidemiology Unit
  • Eleni SofianopoulouUniversity of Cambridge; National Institute for Health and Care Research
  • Stephen J. SharpUniversity of Cambridge; MRC Epidemiology Unit
  • Felix R. DayUniversity of Cambridge; MRC Epidemiology Unit
  • Fumiaki ImamuraUniversity of Cambridge; MRC Epidemiology Unit

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.

Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).

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