Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations
- Ju-Sheng Zheng
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- J. Luan
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- E. Sofianopoulou
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- F. Imamura
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- I. Stewart
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- F. Day
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- M. Pietzner
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- E. Wheeler
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- L. Lotta
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- T. Gundersen
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- P. Amiano
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- E. Ardanaz
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- M. Chirlaque
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- G. Fagherazzi
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- P. Franks
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- R. Kaaks
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- N. Laouali
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- F. Mancini
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- P. Nilsson
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- N. Onland-Moret
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- A. Olsen
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- K. Overvad
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- S. Panico
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- D. Palli
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- F. Ricceri
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- O. Rolandsson
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- A. Spijkerman
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- M. Sánchez
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- M. Schulze
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- N. Sala
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- S. Sieri
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- A. Tjønneland
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- A. Tjønneland
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- R. Tumino
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- Y. T. V. D. Schouw
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- E. Weiderpass
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- E. Riboli
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- J. Danesh
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- A. Butterworth
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- S. Sharp
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- C. Langenberg
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- N. Forouhi
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- N. Wareham
Enhanced Details
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 diabet...
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 × 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.