Rheumatoid 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.
Objectives
To examine the VD-RA causal relationship and investigate androgen/estrogen mediation using Mendelian randomization (MR).
Methods
We conducted two-sample MR analyses using UK Biobank and IEU OpenGWAS data, with genetic variants as instruments. Mediation analyses assessed sex hormone effects.
Results
Dietary 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.
Conclusion
VD may reduce RA risk via gender-specific mechanisms, particularly by decreasing female testosterone. While MR supports causality, potential confounding requires cautious interpretation.
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