Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.
Diabetes care 2020 ; 44: 98-106.
Zheng JS, Luan J, Sofianopoulou E, Imamura F, Stewart ID, Day FR, Pietzner M, Wheeler E, Lotta LA, Gundersen TE, Amiano P, Ardanaz E, Chirlaque MD, 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, Sánchez MJ, Schulze MB, Sala N, Sieri S, Tjønneland A, Tumino R, van der Schouw YT, Weiderpass E, Riboli E, Danesh J, Butterworth AS, Sharp SJ, Langenberg C, Forouhi NG, Wareham NJ
DOI : 10.2337/dc20-1328
PubMed ID : 33203707
PMCID : PMC7783939
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.
Type 2 diabetes is a condition with potentially serious health consequences and therefore the search continues for strategies to prevent the high and rising tide of type 2 diabetes. Previous research indicated that higher blood levels of vitamin C were linked with lower future risk of type 2 diabetes and if this was proven to be cause and effect, it could mean that giving vitamin C as a supplement may help in preventing the condition. Teasing this out is complex. Doing clinical trials where vitamin C is given to one group and not to a control group could help, but trials are very hard and expensive to conduct and there are many challenges, including getting the dose right. In the current research we used a different strategy to get at the answer of whether there is a cause and effect or causal link, using genetics to help us.
First we identified 11 genetic markers that can predict blood levels of vitamin C using a large sample of more than 50,000 adults. Then we tested the association of type 2 diabetes with genetically predicted vitamin C levels with a large sample size of more than 80,000 people with diabetes and up-to 840,000 people without diabetes. We found a mismatch when comparing the link of diabetes with the genetically predicted vitamin C levels versus when we used directly measured blood vitamin C levels. In a research technique called Mendelian randomization, had there been a casual association the findings would have matched in the same direction. Thus our different results for directly measured or genetically predicted blood vitamin C levels indicated that blood vitamin C is not likely to be a causal factor for the development of type diabetes. Therefore we conclude that it is not justified to use vitamin C supplementation for the prevention of type 2 diabetes.
In a separate but relevant point we note that our current research findings should be interpreted as showing no link of the micronutrient vitamin C with type 2 diabetes. However, this should be distinguished from the usefulness of blood vitamin C levels as an objective biomarker in research to complement the subjective reporting of consuming fruit and vegetables, which can be inaccurate and unreliable.