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