Causal association of diet-derived circulating antioxidants with the risk of rheumatoid arthritis: A Mendelian randomization study

Antioxidants, as scavengers of free radicals, have been proposed as potential targets for the prevention and treatment of rheumatoid arthritis (RA), however, the causal associations between antioxidants and RA are still in debate.This study aims to evaluate this causal association with two-sample Mendelian randomization (MR) analysis.Inverse-variance weighted was used as the major analysis method of MR. Genetic variants associated with dietary antioxidants including vitamin E (α- and γ-tocopherol), β-carotene, lycopene, vitamin C (L-ascorbic acid or ascorbate), and retinol, and their circulating metabolites were used as instrumental variables. The causal effects of the antioxidants were assessed in genome-wide association study datasets of RA from a previous publication (Okada Y. et al.) and Finngen consortium and combined with meta-analysis.We observed that the levels of circulating retinol metabolite negatively correlates with the risk of overall RA in the dataset from Okada Y. et al. (odds ratio [OR]=0.952, 95% confidence interval [CI]=0.911-0.996, p = 0.031) and Finngen (OR=0.946, 95%CI=0.903-0.991, p = 0.020). The causal association remained consistent in the meta-analysis (OR=0.949, 95%CI=0.919-0.98, p = 0.002). Increased levels of circulating retinol metabolite also suggestively decreased the risk of seropositive RA (OR=0.936, 95%CI=0.884-0.992, p = 0.025) but not seronegative RA (OR=0.996, 95%CI=0.921-1.076, p = 0.913). No causal effects of other dietary antioxidants on RA were identified in our analyses.Our study suggested a protective effect of circulating retinol metabolites, but not other antioxidants, on overall RA and seropositive RA. Dietary supplementation of retinol may be an effective measure for the primary prevention of RA.