Vitamin D and rheumatoid arthritis in European populations: Unraveling causal links and the mediating role of sex hormones via Mendelian randomization

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease causing joint damage and disability. Vitamin D (VD) shows immunomodulatory effects in RA, but its causal role and potential mediation by sex hormones remain unclear.ObjectivesTo examine the VD-RA causal relationship and investigate androgen/estrogen mediation using Mendelian randomization (MR).MethodsWe conducted two-sample MR analyses using UK Biobank and IEU OpenGWAS data, with genetic variants as instruments. Mediation analyses assessed sex hormone effects.ResultsDietary VD associated with reduced RA risk (odds ratio (OR) = 0.994, 95%CI 0.992-0.996). Protective effects were stronger in males with seropositive RA (OR = 0.97, 95%CI 0.96-0.99) and females with seronegative RA (OR = 0.99, 95%CI 0.98-0.99). VD significantly lowered female testosterone (OR = 0.54, 95%CI 0.42-0.66), a RA risk factor (OR = 1.03, 95%CI 1.01-1.04), but did not affect male testosterone or female estrogen levels.ConclusionVD may reduce RA risk via gender-specific mechanisms, particularly by decreasing female testosterone. While MR supports causality, potential confounding requires cautious interpretation.