Exploring the link between dietary vitamin C intake and rheumatoid arthritis risk: A mendelian randomization analysis based on the National Health and Nutrition Examination Survey 2009-2018.

Prior studies on dietary vitamin C and rheumatoid arthritis (RA) risk are inconsistent and confounded by lifestyle and reverse causation, leaving causality unclear. To address this knowledge gap, this study aimed to investigate whether higher dietary vitamin C intake is associated with lower RA risk and whether this association reflects a causal protective effect. Given that vitamin C deficiency is common in patients with RA, this study analyzed data from 49,693 participants in 2009 to 2018 National Health and Nutrition Examination Survey (NHANES) database to investigate the association between vitamin C intake and the disease. The National Health and Nutrition Examination Survey is the only U.S. national survey to provide clinical, laboratory, and nutritional data for participants of all ages. The participants were divided into quartiles based on interquartile ranges. With adjustment for all covariates, the Q3 (106.71 ± 24.81 mg/d) odds ratio = 0.937, 95% confidence interval (CI): 0.936-0.938, P < .001) and Q4 groups (560.61 ± 353.41 mg/day) odds ratio = 0.940, 95% CI: 0.939-0.942, P < .001) presented significantly lower risks of RA occurrence compared with the Q1 group (20.47 ± 11.99 mg/day). To overcome confounding and assess causality, we employed 2-sample mendelian randomization (MR) using genetic variants as instrumental variables. The inverse variance weighted method with MR revealed no significant relationship between RA and vitamin C (OR = 0.932, 95% CI: 0.596-1.458, P = .796). After adjusting for covariates (age, educational level, and medical history), the risk of RA in women was found to be significantly higher than that in men (OR = 1.534, 95% CI: 1.527-1.531, P < .001). However, after further adjustment for vitamin C intake, this risk showed a slight reduction (OR = 1.529, 95% CI: 1.527-1.531, P < .001). Two-sample MR revealed 24 proteins associated with RA. The findings on target intersection suggested the possible influence of vitamin C on RA through retinol dehydrogenase 16 and acid phosphatase 1though their synovial tissue expression (GSE55235) showed no significant differences in RA patients. This study provides observational evidence linking higher dietary vitamin C intake to lower RA risk, but MR found no causal relationship, suggesting confounding.