Association of plasma Vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study

Ju Sheng Zheng, Fumiaki Imamura, Stephen J. Sharp, Yvonne T. Van Der Schouw, Ivonne Sluijs, Thomas E. Gundersen, Eva Ardanaz, Heiner Boeing, Catalina Bonet, Jesus Humberto Gómez, Courtney Dow, Guy Fagherazzi, Paul W. Franks, Mazda Jenab, Tilman Kuhn, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Cristina Lasheras, Olatz MokoroaFrancesca Romana Mancini, Peter M. Nilsson, Kim Overvad, Salvatore Panico, Domenico Palli, Olov Rolandsson, Sabina Sieri, Elena Salamanca-Fernández, Carlotta Sacerdote, Annemieke M.W. Spijkerman, Magdalena Stepien, Anne Tjonneland, Rosario Tumino, Adam S. Butterworth, Elio Riboli, John Danesh, Claudia Langenberg, Nita G. Forouhi, Nicholas J. Wareham

Research output: Contribution to journalArticle

Abstract

Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: Nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

Original languageEnglish
Pages (from-to)1293-1303
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

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Nutrition
Medical problems
Metabolites
Vitamin D
Type 2 Diabetes Mellitus
Cohort Studies
Plasmas
Neoplasms
Hazards
Association reactions
Stereoisomerism
Liquid chromatography
Liquid Chromatography
Meta-Analysis
Mass Spectrometry
Mass spectrometry

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Zheng, J. S., Imamura, F., Sharp, S. J., Van Der Schouw, Y. T., Sluijs, I., Gundersen, T. E., ... Wareham, N. J. (2019). Association of plasma Vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study. Journal of Clinical Endocrinology and Metabolism, 104(4), 1293-1303. https://doi.org/10.1210/jc.2018-01522

Association of plasma Vitamin D metabolites with incident type 2 diabetes : EPIC-InterAct case-cohort study. / Zheng, Ju Sheng; Imamura, Fumiaki; Sharp, Stephen J.; Van Der Schouw, Yvonne T.; Sluijs, Ivonne; Gundersen, Thomas E.; Ardanaz, Eva; Boeing, Heiner; Bonet, Catalina; Gómez, Jesus Humberto; Dow, Courtney; Fagherazzi, Guy; Franks, Paul W.; Jenab, Mazda; Kuhn, Tilman; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay Tee; Lasheras, Cristina; Mokoroa, Olatz; Mancini, Francesca Romana; Nilsson, Peter M.; Overvad, Kim; Panico, Salvatore; Palli, Domenico; Rolandsson, Olov; Sieri, Sabina; Salamanca-Fernández, Elena; Sacerdote, Carlotta; Spijkerman, Annemieke M.W.; Stepien, Magdalena; Tjonneland, Anne; Tumino, Rosario; Butterworth, Adam S.; Riboli, Elio; Danesh, John; Langenberg, Claudia; Forouhi, Nita G.; Wareham, Nicholas J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 104, No. 4, 01.04.2019, p. 1293-1303.

Research output: Contribution to journalArticle

Zheng, JS, Imamura, F, Sharp, SJ, Van Der Schouw, YT, Sluijs, I, Gundersen, TE, Ardanaz, E, Boeing, H, Bonet, C, Gómez, JH, Dow, C, Fagherazzi, G, Franks, PW, Jenab, M, Kuhn, T, Kaaks, R, Key, TJ, Khaw, KT, Lasheras, C, Mokoroa, O, Mancini, FR, Nilsson, PM, Overvad, K, Panico, S, Palli, D, Rolandsson, O, Sieri, S, Salamanca-Fernández, E, Sacerdote, C, Spijkerman, AMW, Stepien, M, Tjonneland, A, Tumino, R, Butterworth, AS, Riboli, E, Danesh, J, Langenberg, C, Forouhi, NG & Wareham, NJ 2019, 'Association of plasma Vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 4, pp. 1293-1303. https://doi.org/10.1210/jc.2018-01522
Zheng, Ju Sheng ; Imamura, Fumiaki ; Sharp, Stephen J. ; Van Der Schouw, Yvonne T. ; Sluijs, Ivonne ; Gundersen, Thomas E. ; Ardanaz, Eva ; Boeing, Heiner ; Bonet, Catalina ; Gómez, Jesus Humberto ; Dow, Courtney ; Fagherazzi, Guy ; Franks, Paul W. ; Jenab, Mazda ; Kuhn, Tilman ; Kaaks, Rudolf ; Key, Timothy J. ; Khaw, Kay Tee ; Lasheras, Cristina ; Mokoroa, Olatz ; Mancini, Francesca Romana ; Nilsson, Peter M. ; Overvad, Kim ; Panico, Salvatore ; Palli, Domenico ; Rolandsson, Olov ; Sieri, Sabina ; Salamanca-Fernández, Elena ; Sacerdote, Carlotta ; Spijkerman, Annemieke M.W. ; Stepien, Magdalena ; Tjonneland, Anne ; Tumino, Rosario ; Butterworth, Adam S. ; Riboli, Elio ; Danesh, John ; Langenberg, Claudia ; Forouhi, Nita G. ; Wareham, Nicholas J. / Association of plasma Vitamin D metabolites with incident type 2 diabetes : EPIC-InterAct case-cohort study. In: Journal of Clinical Endocrinology and Metabolism. 2019 ; Vol. 104, No. 4. pp. 1293-1303.
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abstract = "Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: Nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95{\%} CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.",
author = "Zheng, {Ju Sheng} and Fumiaki Imamura and Sharp, {Stephen J.} and {Van Der Schouw}, {Yvonne T.} and Ivonne Sluijs and Gundersen, {Thomas E.} and Eva Ardanaz and Heiner Boeing and Catalina Bonet and G{\'o}mez, {Jesus Humberto} and Courtney Dow and Guy Fagherazzi and Franks, {Paul W.} and Mazda Jenab and Tilman Kuhn and Rudolf Kaaks and Key, {Timothy J.} and Khaw, {Kay Tee} and Cristina Lasheras and Olatz Mokoroa and Mancini, {Francesca Romana} and Nilsson, {Peter M.} and Kim Overvad and Salvatore Panico and Domenico Palli and Olov Rolandsson and Sabina Sieri and Elena Salamanca-Fern{\'a}ndez and Carlotta Sacerdote and Spijkerman, {Annemieke M.W.} and Magdalena Stepien and Anne Tjonneland and Rosario Tumino and Butterworth, {Adam S.} and Elio Riboli and John Danesh and Claudia Langenberg and Forouhi, {Nita G.} and Wareham, {Nicholas J.}",
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TY - JOUR

T1 - Association of plasma Vitamin D metabolites with incident type 2 diabetes

T2 - EPIC-InterAct case-cohort study

AU - Zheng, Ju Sheng

AU - Imamura, Fumiaki

AU - Sharp, Stephen J.

AU - Van Der Schouw, Yvonne T.

AU - Sluijs, Ivonne

AU - Gundersen, Thomas E.

AU - Ardanaz, Eva

AU - Boeing, Heiner

AU - Bonet, Catalina

AU - Gómez, Jesus Humberto

AU - Dow, Courtney

AU - Fagherazzi, Guy

AU - Franks, Paul W.

AU - Jenab, Mazda

AU - Kuhn, Tilman

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Khaw, Kay Tee

AU - Lasheras, Cristina

AU - Mokoroa, Olatz

AU - Mancini, Francesca Romana

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Panico, Salvatore

AU - Palli, Domenico

AU - Rolandsson, Olov

AU - Sieri, Sabina

AU - Salamanca-Fernández, Elena

AU - Sacerdote, Carlotta

AU - Spijkerman, Annemieke M.W.

AU - Stepien, Magdalena

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - Butterworth, Adam S.

AU - Riboli, Elio

AU - Danesh, John

AU - Langenberg, Claudia

AU - Forouhi, Nita G.

AU - Wareham, Nicholas J.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: Nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

AB - Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: Nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

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