Diet-derived circulating antioxidants and risk of knee osteoarthritis, hip osteoarthritis and rheumatoid arthritis: a two-sample Mendelian randomization study.

Objective: To examine the causal associations of diet-derived circulating antioxidants with knee osteoarthritis (OA), hip OA, and rheumatoid arthritis (RA) within the two-sample Mendelian randomization (MR) framework. Method: Independent single-nucleotide polymorphisms (SNPs) significantly associated with circulating levels of diet-derived antioxidants (retinol, ß-carotene, lycopene, vitamin C and vitamin E) were extracted as genetic instruments. Summary statistics of genetic instruments associated with knee OA, hip OA, and RA were obtained from corresponding genome-wide association studies (GWASs). The inverse-variance weighted (IVW) was applied as the primary analysis method, with four sensitivity analysis approaches employed to evaluate the robustness of the primary results. Results: Genetically determined per unit increment of absolute circulating levels of retinol was significantly associated with a reduced risk of hip OA [odds ratio (OR) = 0.45, 95% confidence interval (CI) 0.26-0.78, p = 4.43 × 10-3], while genetically determined per unit increase in absolute circulating levels of ß-carotene was suggestively associated with increased risk of RA (OR = 1.32, 95% CI 1.07-1.62, p = 9.10 × 10-3). No other causal association was found. Significant evidence for heterogeneity and pleiotropic outlier was only identified when absolute circulating vitamin C was evaluated as the exposure, whereas all sensitive analysis provided consistently non-significant results. Conclusion: Our results demonstrated that genetically determined lifelong higher exposure to absolute circulating levels of retinol is associated with a decreased risk of hip OA. Further MR study with more genetic instruments for absolute circulating levels of antioxidants are needed to confirm our results.