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

Adults of European ancestry from multiple cohorts (Fenland, EPIC-InterAct, EPIC-Norfolk, EPIC-CVD, UK Biobank, and DIAMANTE). Designs included a GWAS meta-analysis to identify variants for plasma vitamin C (52,018 participants); two-sample Mendelian randomization using lead variants to assess causal effect of genetically predicted plasma vitamin C on type 2 diabetes risk (80,983 cases; 842,909 noncases); and an observational analysis of plasma vitamin C and incident type 2 diabetes in EPIC-InterAct (case-cohort design) with 8,133 cases and 11,073 noncases.

Observationally, plasma vitamin C is inversely associated with incident type 2 diabetes (HR 0.88 per 1-SD; 95% CI 0.82–0.94). Genetically predicted higher plasma vitamin C is not associated with type 2 diabetes risk (OR 1.03 per 1-SD; 95% CI 0.96–1.10) after excluding the FADS1 variant due to pleiotropy. No evidence of directional pleiotropy; MR sensitivity analyses yielded similar results. There is discordance between biochemically measured and genetically predicted plasma vitamin C in relation to type 2 diabetes; No strong evidence that vitamin C supplementation prevents type 2 diabetes in European populations. Observational inverse associations may reflect dietary patterns (e.g., fruit/vegetable intake) rather than a causal effect of vitamin C; plasma vitamin C can serve as a biomarker of fruit/vegetable intake rather than a causal nutrient for diabetes risk.

Lead SNPs explained ~1.87% of plasma vitamin C variance (mean); instrument strength adequate (F statistic ~30.5) but explained variance is small, potentially limiting power. Analyses restricted to White European populations; residual pleiotropy cannot be fully ruled out despite tests; MR estimates could be biased by gene–environment interactions or canalization.