Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Ju-Sheng Zheng; Jian'an Luan; Eleni Sofianopoulou; Fumiaki Imamura; Isobel D. Stewart; Felix R. Day; Maik Pietzner; Eleanor Wheeler; Luca A. Lotta; Thomas E. Gundersen; Pilar Amiano; Eva Ardanaz; Maria-Dolores Chirlaque; Guy Fagherazzi; Paul W. Franks; Rudolf Kaaks; Nasser Laouali; Francesca Romana Mancini; Peter M. Nilsson; N. Charlotte Onland-Moret; Anja Olsen; Kim Overvad; Salvatore Panico; Domenico Palli; Fulvio Ricceri; Olov Rolandsson; Annemieke M. W. Spijkerman; Maria-Jose Sanchez; Matthias B. Schulze; Nuria Sala; Sabina Sieri; Anne Tjonneland; Rosario Tumino; Yvonne T. van der Schouw; Elisabete Weiderpass; Elio Riboli; John Danesh; Adam S. Butterworth; Stephen J. Sharp; Claudia Langenberg; Nita G. Forouhi; Nicholas J. Wareham

doi:10.2337/dc20-1328

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Ju-Sheng Zheng, Jian'an Luan, Eleni Sofianopoulou, Fumiaki Imamura, Isobel D. Stewart, Felix R. Day, Maik Pietzner, Eleanor Wheeler, Luca A. Lotta, Thomas E. Gundersen, Pilar Amiano, Eva Ardanaz, Maria-Dolores Chirlaque, Guy Fagherazzi, Paul W. Franks, Rudolf Kaaks, Nasser Laouali, Francesca Romana Mancini, Peter M. Nilsson, N. Charlotte Onland-MoretAnja Olsen, Kim Overvad, Salvatore Panico, Domenico Palli, Fulvio Ricceri, Olov Rolandsson, Annemieke M. W. Spijkerman, Maria-Jose Sanchez, Matthias B. Schulze, Nuria Sala, Sabina Sieri, Anne Tjonneland, Rosario Tumino, Yvonne T. van der Schouw, Elisabete Weiderpass, Elio Riboli, John Danesh, Adam S. Butterworth, Stephen J. Sharp, Claudia Langenberg, Nita G. Forouhi, Nicholas J. Wareham

Section of Environmental Health

Research output: Contribution to journal › Journal article › Research › peer-review

125 Citations (Scopus)

Abstract

OBJECTIVE

Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.

RESULTS

We identified 11 genomic regions associated with plasma vitamin C (P <5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

CONCLUSIONS

These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

Original language	English
Journal	Diabetes Care. Supplement
Volume	44
Issue number	1
Pages (from-to)	98-106
Number of pages	9
ISSN	0149-5992
DOIs	https://doi.org/10.2337/dc20-1328
Publication status	Published - Jan 2021

Keywords

GENETIC-VARIATION
ASCORBIC-ACID
OXIDATIVE STRESS
VEGETABLE INTAKE
EPIC-NORFOLK
LIFE-STYLE
METAANALYSIS
FRUIT
DESIGN
LEVEL

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783939/pdf/dc201328.pdfLicence: Other

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Zheng, J.-S., Luan, J., Sofianopoulou, E., Imamura, F., Stewart, I. D., Day, F. R., Pietzner, M., Wheeler, E., Lotta, L. A., Gundersen, T. E., Amiano, P., Ardanaz, E., Chirlaque, M.-D., Fagherazzi, G., Franks, P. W., Kaaks, R., Laouali, N., Mancini, F. R., Nilsson, P. M., ... Wareham, N. J. (2021). Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations. Diabetes Care. Supplement, 44(1), 98-106. https://doi.org/10.2337/dc20-1328

Zheng, J-S, Luan, J, Sofianopoulou, E, Imamura, F, Stewart, ID, Day, FR, Pietzner, M, Wheeler, E, Lotta, LA, Gundersen, TE, Amiano, P, Ardanaz, E, Chirlaque, M-D, Fagherazzi, G, Franks, PW, Kaaks, R, Laouali, N, Mancini, FR, Nilsson, PM, Onland-Moret, NC, Olsen, A, Overvad, K, Panico, S, Palli, D, Ricceri, F, Rolandsson, O, Spijkerman, AMW, Sanchez, M-J, Schulze, MB, Sala, N, Sieri, S, Tjonneland, A, Tumino, R, van der Schouw, YT, Weiderpass, E, Riboli, E, Danesh, J, Butterworth, AS, Sharp, SJ, Langenberg, C, Forouhi, NG & Wareham, NJ 2021, 'Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations', Diabetes Care. Supplement, vol. 44, no. 1, pp. 98-106. https://doi.org/10.2337/dc20-1328

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title = "Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations",

abstract = "OBJECTIVEHigher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.RESULTSWe identified 11 genomic regions associated with plasma vitamin C (P <5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).CONCLUSIONSThese findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.",

keywords = "GENETIC-VARIATION, ASCORBIC-ACID, OXIDATIVE STRESS, VEGETABLE INTAKE, EPIC-NORFOLK, LIFE-STYLE, METAANALYSIS, FRUIT, DESIGN, LEVEL",

author = "Ju-Sheng Zheng and Jian'an Luan and Eleni Sofianopoulou and Fumiaki Imamura and Stewart, {Isobel D.} and Day, {Felix R.} and Maik Pietzner and Eleanor Wheeler and Lotta, {Luca A.} and Gundersen, {Thomas E.} and Pilar Amiano and Eva Ardanaz and Maria-Dolores Chirlaque and Guy Fagherazzi and Franks, {Paul W.} and Rudolf Kaaks and Nasser Laouali and Mancini, {Francesca Romana} and Nilsson, {Peter M.} and Onland-Moret, {N. Charlotte} and Anja Olsen and Kim Overvad and Salvatore Panico and Domenico Palli and Fulvio Ricceri and Olov Rolandsson and Spijkerman, {Annemieke M. W.} and Maria-Jose Sanchez and Schulze, {Matthias B.} and Nuria Sala and Sabina Sieri and Anne Tjonneland and Rosario Tumino and {van der Schouw}, {Yvonne T.} and Elisabete Weiderpass and Elio Riboli and John Danesh and Butterworth, {Adam S.} and Sharp, {Stephen J.} and Claudia Langenberg and Forouhi, {Nita G.} and Wareham, {Nicholas J.}",

year = "2021",

month = jan,

doi = "10.2337/dc20-1328",

language = "English",

volume = "44",

pages = "98--106",

journal = "Diabetes Care. Supplement",

issn = "0149-5992",

publisher = "American Diabetes Association",

number = "1",

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TY - JOUR

T1 - Plasma Vitamin C and Type 2 Diabetes

T2 - Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

AU - Zheng, Ju-Sheng

AU - Luan, Jian'an

AU - Sofianopoulou, Eleni

AU - Imamura, Fumiaki

AU - Stewart, Isobel D.

AU - Day, Felix R.

AU - Pietzner, Maik

AU - Wheeler, Eleanor

AU - Lotta, Luca A.

AU - Gundersen, Thomas E.

AU - Amiano, Pilar

AU - Ardanaz, Eva

AU - Chirlaque, Maria-Dolores

AU - Fagherazzi, Guy

AU - Franks, Paul W.

AU - Kaaks, Rudolf

AU - Laouali, Nasser

AU - Mancini, Francesca Romana

AU - Nilsson, Peter M.

AU - Onland-Moret, N. Charlotte

AU - Olsen, Anja

AU - Overvad, Kim

AU - Panico, Salvatore

AU - Palli, Domenico

AU - Ricceri, Fulvio

AU - Rolandsson, Olov

AU - Spijkerman, Annemieke M. W.

AU - Sanchez, Maria-Jose

AU - Schulze, Matthias B.

AU - Sala, Nuria

AU - Sieri, Sabina

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - van der Schouw, Yvonne T.

AU - Weiderpass, Elisabete

AU - Riboli, Elio

AU - Danesh, John

AU - Butterworth, Adam S.

AU - Sharp, Stephen J.

AU - Langenberg, Claudia

AU - Forouhi, Nita G.

AU - Wareham, Nicholas J.

PY - 2021/1

Y1 - 2021/1

N2 - OBJECTIVEHigher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.RESULTSWe identified 11 genomic regions associated with plasma vitamin C (P <5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).CONCLUSIONSThese findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

AB - OBJECTIVEHigher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.RESULTSWe identified 11 genomic regions associated with plasma vitamin C (P <5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).CONCLUSIONSThese findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

KW - GENETIC-VARIATION

KW - ASCORBIC-ACID

KW - OXIDATIVE STRESS

KW - VEGETABLE INTAKE

KW - EPIC-NORFOLK

KW - LIFE-STYLE

KW - METAANALYSIS

KW - FRUIT

KW - DESIGN

KW - LEVEL

U2 - 10.2337/dc20-1328

DO - 10.2337/dc20-1328

M3 - Journal article

C2 - 33203707

SN - 0149-5992

VL - 44

SP - 98

EP - 106

JO - Diabetes Care. Supplement

JF - Diabetes Care. Supplement

IS - 1

ER -