TY - JOUR
T1 - The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations
T2 - 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 - Ramón Quirós, J.
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.
N1 - Funding Information:
The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197). Biomarker measurements for vitamin D metabolites were funded jointly by the InterAct project, the EPIC-CVD project and the MRC Cambridge Initiative (RG71466, SJAH/004). EPIC-CVD has been supported by the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTHF2-2012-279233), the European Research Council (268834) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). JD is funded by the National Institute for Health Research (Senior Investigator Award). NJW and NGF acknowledge funding from the following agencies: Medical Research Council Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5, and NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). JSZ has received funding from Westlake University (No. YSYY0209) and the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701708. EA has received funding from Health Research Fund (FIS) of the Spanish Ministry of Health and Navarre Regional Government. PWF has received funding from Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation, European Research Council. JMH has received funding from Health Research Fund of the Spanish Ministry of Health; Murcia Regional Government (Nº6236). PJ has received funding from the Health Research Funds - RD12/0036/0018 and AGAUR, Generalitat de Catalunya (exp. 2014 SGR 726). RK has received funding from German Cancer Aid, German Ministry of Research (BMBF). KTK has received funding from Medical Research Council UK, Cancer Research UK. TK has received funding from German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF). PMN has received funding from Swedish Research Council. KO has received funding from Danish Cancer Society. SP has received funding from Compagnia di San Paolo. JRQ has received funding from Regional Government of Asturias. OR has received funding from the Västerboten County Council. TYNT has received funding from the Cancer Research UK (C570/A16491 and C8221/A19170), UK Medical Research Council (MR/M012190/1).
Publisher Copyright:
Copyright: © 2020 Zheng et al.
PY - 2020/10/16
Y1 - 2020/10/16
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85093706249&partnerID=8YFLogxK
U2 - 10.1371/journal.pmed.1003394
DO - 10.1371/journal.pmed.1003394
M3 - Article
C2 - 33064751
AN - SCOPUS:85093706249
SN - 1549-1277
VL - 17
JO - PLoS Medicine
JF - PLoS Medicine
IS - 10
M1 - e1003394
ER -
