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

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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. / Zheng, Ju-Sheng; Luan, Jian'an; Sofianopoulou, Eleni; Sharp, Stephen J; Day, Felix R; Imamura, Fumiaki; Gundersen, Thomas E; Lotta, Luca A; Sluijs, Ivonne; Stewart, Isobel D; Shah, Rupal L; van der Schouw, Yvonne T; Wheeler, Eleanor; Ardanaz, Eva; Boeing, Heiner; Dorronsoro, Miren; Dahm, Christina C; Dimou, Niki; El-Fatouhi, Douae; Franks, Paul W; Fagherazzi, Guy; Grioni, Sara; Huerta, José María; Heath, Alicia K; Hansen, Louise; Jenab, Mazda; Jakszyn, Paula; Kaaks, Rudolf; Kühn, Tilman; Khaw, Kay-Tee; Laouali, Nasser; Masala, Giovanna; Nilsson, Peter M; Overvad, Kim; Olsen, Anja; Panico, Salvatore; Quirós, J Ramón; Rolandsson, Olov; Rodríguez-Barranco, Miguel; Sacerdote, Carlotta; Spijkerman, Annemieke M W; Tong, Tammy Y N; Tumino, Rosario; Tsilidis, Konstantinos K; Danesh, John; Riboli, Elio; Butterworth, Adam S; Langenberg, Claudia; Forouhi, Nita G; Wareham, Nicholas J.

I: PLOS Medicine, Bind 17, Nr. 10, e1003394, 10.2020.

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

Harvard

Zheng, J-S, 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, K-T, 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 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, bind 17, nr. 10, e1003394. https://doi.org/10.1371/journal.pmed.1003394

APA

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

CBE

Zheng J-S, 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 K-T, 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. 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):Article e1003394. https://doi.org/10.1371/journal.pmed.1003394

MLA

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Author

Zheng, Ju-Sheng ; Luan, Jian'an ; Sofianopoulou, Eleni ; Sharp, Stephen J ; Day, Felix R ; Imamura, Fumiaki ; Gundersen, Thomas E ; Lotta, Luca A ; Sluijs, Ivonne ; Stewart, Isobel D ; Shah, Rupal L ; van der Schouw, Yvonne T ; Wheeler, Eleanor ; Ardanaz, Eva ; Boeing, Heiner ; Dorronsoro, Miren ; Dahm, Christina C ; Dimou, Niki ; El-Fatouhi, Douae ; Franks, Paul W ; Fagherazzi, Guy ; Grioni, Sara ; Huerta, José María ; Heath, Alicia K ; Hansen, Louise ; Jenab, Mazda ; Jakszyn, Paula ; Kaaks, Rudolf ; Kühn, Tilman ; Khaw, Kay-Tee ; Laouali, Nasser ; Masala, Giovanna ; Nilsson, Peter M ; Overvad, Kim ; Olsen, Anja ; Panico, Salvatore ; Quirós, J Ramón ; Rolandsson, Olov ; Rodríguez-Barranco, Miguel ; Sacerdote, Carlotta ; Spijkerman, Annemieke M W ; Tong, Tammy Y N ; Tumino, Rosario ; Tsilidis, Konstantinos K ; Danesh, John ; Riboli, Elio ; Butterworth, Adam S ; Langenberg, Claudia ; Forouhi, Nita G ; Wareham, Nicholas J. / The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations : A meta-analysis and Mendelian randomisation analysis. I: PLOS Medicine. 2020 ; Bind 17, Nr. 10.

Bibtex

@article{8357f02e887c4ca4bb47b982ae8e13ea,
title = "The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis",
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.",
author = "Ju-Sheng Zheng and Jian'an Luan and Eleni Sofianopoulou and Sharp, {Stephen J} and Day, {Felix R} and Fumiaki Imamura and Gundersen, {Thomas E} and Lotta, {Luca A} and Ivonne Sluijs and Stewart, {Isobel D} and Shah, {Rupal L} and {van der Schouw}, {Yvonne T} and Eleanor Wheeler and Eva Ardanaz and Heiner Boeing and Miren Dorronsoro and Dahm, {Christina C} and Niki Dimou and Douae El-Fatouhi and Franks, {Paul W} and Guy Fagherazzi and Sara Grioni and Huerta, {Jos{\'e} Mar{\'i}a} and Heath, {Alicia K} and Louise Hansen and Mazda Jenab and Paula Jakszyn and Rudolf Kaaks and Tilman K{\"u}hn and Kay-Tee Khaw and Nasser Laouali and Giovanna Masala and Nilsson, {Peter M} and Kim Overvad and Anja Olsen and Salvatore Panico and Quir{\'o}s, {J Ram{\'o}n} and Olov Rolandsson and Miguel Rodr{\'i}guez-Barranco and Carlotta Sacerdote and Spijkerman, {Annemieke M W} and Tong, {Tammy Y N} and Rosario Tumino and Tsilidis, {Konstantinos K} and John Danesh and Elio Riboli and Butterworth, {Adam S} and Claudia Langenberg and Forouhi, {Nita G} and Wareham, {Nicholas J}",
year = "2020",
month = oct,
doi = "10.1371/journal.pmed.1003394",
language = "English",
volume = "17",
journal = "P L o S Medicine (Online)",
issn = "1549-1277",
publisher = "public library of science",
number = "10",

}

RIS

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 - 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

PY - 2020/10

Y1 - 2020/10

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.

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.

U2 - 10.1371/journal.pmed.1003394

DO - 10.1371/journal.pmed.1003394

M3 - Journal article

C2 - 33064751

VL - 17

JO - P L o S Medicine (Online)

JF - P L o S Medicine (Online)

SN - 1549-1277

IS - 10

M1 - e1003394

ER -