Abstract
BACKGROUND: Observational studies indicated potential associations between primary biliary cholangitis (PBC) and rheumatoid arthritis (RA). However, the causal relationship between RA and PBC remains unclear and controversial. The aim of this study was to evaluate the causal relationships among seropositive RA (SPRA), seronegative RA (SNRA) and PBC. METHODS: This study employed a Mendelian randomization (MR) framework to analyze genome-wide association study (GWAS) data from a European population. The dataset included 802 cases and 16,489 controls for PBC, 18,019 cases and 991,604 controls for SPRA, and 8,515 cases and 1,015,471 controls for SNRA, retrieved on June 11, 2024. Instrumental variables (IVs) were selected based on genome-wide significance (P < 5.0E-08) and independence (R(2) < 0.001). Palindromic and incompatible SNPs were excluded, and weak instruments (F < 10) were removed. Inverse variance weighting (IVW) was the primary analysis method, complemented by Bayesian weighted MR (BWMR), robustly adjusted profile scores (MR-RAPS), MR-Egger, and weighted median approaches. Sensitivity analyses included Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis to assess the robustness of the results. RESULTS: SPRA increased the risk of genetic susceptibility to PBC (OR=1.28, 95% CI 1.10-1.4, P =0.001). No causal effect of the SNRA on PBC risk was observed. CONCLUSION: Our findings show that SPRA increases the risk of developing with PBC. This will help inform future screening guidelines for associated PBC in patients with RA.