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

• Published in: Diabetes care Vol. 44; no. 1; pp. 98 - 106
• Main Authors: 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, María-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, Sánchez, María-José, Schulze, Matthias B, Sala, Núria, Sieri, Sabina, Tjønneland, 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-01-2021
• Subjects: AKT1 protein; Ascorbic acid; Ascorbic Acid - blood; Basic Medicine; Clinical Medicine; Delta-5 Fatty Acid Desaturase; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Discordance; Disease control; Endocrinology and Diabetes; Endokrinologi och diabetes; Epidemiology/Health Services Research; Genetic analysis; Genetic diversity; Genetic variance; Genome-Wide Association Study; Genomes; Health risks; Humans; Klinisk medicin; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mendelian Randomization Analysis; Plasma; Polymorphism, Single Nucleotide; Populations; Randomization; Research design; Risk Factors; Supplements; Vitamin C
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc20-1328

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.
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.
We identified 11 genomic regions associated with plasma vitamin C (
< 5 × 10
), with the strongest signal at
, and 10 novel genetic loci including
,
,
,
,
,
,
,
,
, and
. 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
variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).
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.