Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

Background: An association between rheumatoid arthritis (RA) and autoimmune liver diseases (AILDs) was found in observational studies. However, neither the direction nor the cause-effect chain was clear. This study aimed to assess the causal associations between AILDs and RA.Methods: We performed a two-sample Mendelian randomization (MR) analysis. Following a strict assessment, genome-wide association study (GWAS) datasets were used to select potential candidate single-nucleotide polymorphisms. The inverse-variance weighted (IVW) was used as the primary analysis approach, supple-mented with four sensitive analysis methods applied to assess the robustness of the results.Results: We discovered that a genetically increased primary biliary cholangitis (PBC) risk had a positive causal effect on RA (IVW OR=1.149, 95% CI=1.063-1.241, P<0.001). According to the MR-Egger regression, hori-zontal pleiotropy was unlikely to impact causality (intercept =-0.028, P = 0.263). Using the leave-one-out strategy, sensitivity studies revealed that the MR analysis results were robust and reliable. Genetically deter-mined primary sclerosing cholangitis (PSC) was not linked with the risk of RA (IVW OR=1.071, 95% CI=0.984-1.166, P = 0.111). The results of the MR analysis were further validated by sensitivity analyses uti-lizing the leave-one-out approach. In the other direction, there was no causal relationship between RA and PBC (OR=1.132, 95% CI=0.881-1.454, P = 0.333) or PSC (OR=1.067, 95% CI=0.891-1.279, P = 0.088).Conclusions: Using a two-sample MR analysis, we investigated the relationship between AILDs and RA and revealed first that PBC increases the risk of RA. Large-scale cross-disease GWAS are required to further illuminate the genomic landscape of AILDs and RA.

Automated summary

By using a two-sample Mendelian randomization analysis, this study revealed a positive causal effect of genetically increased primary biliary cholangitis (PBC) risk on rheumatoid arthritis (RA). However, there was no association between genetically determined primary sclerosing cholangitis (PSC) and RA. The results suggest an increased risk of RA with PBC.