Genetic link between primary biliary cholangitis and connective tissue diseases in European populations: A two-sample Mendelian randomization study

Background An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), systemic sclerosis (SSc) has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. Methods A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls, and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. Results The IVW revealed that genetically predicted PBC increased the risk of SLE odd’s ratio (OR) = 1.43, 95% confidence interval (CI) 1.30–1.58, P < 0.001), RA (OR = 1.09, 95%CI1.04–1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12–1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. Conclusions Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC.