Causal associations between inflammatory bowel disease and primary biliary cholangitis: a two-sample bidirectional Mendelian randomization study

Abstract

Inflammatory bowel disease (IBD) has been reported to be associated with hepatobiliary diseases. Previous observational and Mendelian randomization (MR) studies have suggested a causal association between IBD and primary sclerosing cholangitis (PSC). However, it is unclear whether IBD has a causal association with primary biliary cholangitis (PBC): another autoimmune liver disease. We obtained genome-wide association study (GWAS) statistics from published GWASs for PBC, UC, and CD. We screened qualified instrumental variables (IVs) based on the three major assumptions of MR. To determine the causal relationships between UC or CD and PBC, two-sample MR analyses were performed using inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods, and sensitivity analyses were conducted to validate the robustness of the results. We also conducted reverse MR analysis to reveal the causal association between PBC and UC or CD. UC was associated with a higher risk of PBC (OR 1.35, 95% CI 1.05–1.73, P = 0.02) in the IVW method, and CD was associated with an increased risk of PBC (OR 1.18, 95% CI 1.03–1.36, P = 0.02) in IVW. The weighted median and MR-Egger regression of both diseases showed a consistent direction but were not statistically significant. Results of the reverse MR analysis did not suggest genetic susceptibility that PBC was associated with an increased risk of UC (OR 1.05, 95% CI 0.95–1.17, P = 0.34) or CD (OR 1.1, 95% CI 0.99–1.20, P = 0.06). The present study revealed that IBD subtypes could increase the incidence of PBC, but in turn, PBC did not increase the incidence of IBD subtypes. Understanding that IBD and PBC constitute mutual risk factors can help with the clinical management of both diseases.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization

“…Compared to Zhang 9 , we conducted a study with larger sample sizes and achieved inconsistent estimates across the four statistical methods used. In contrast to the findings of Zhao et al 41 , we emphasized the positive promoting effect of PBC on UC onset. This discrepancy might be attributed to the use of larger sample size GWAS data for PBC and the exclusion of loci within the MHC region that could interfere with causal inference.…”

Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study

“…Given that PSC-IBD is associated with a higher risk of malignancy [ 74 ], timely identification of high-risk individuals and the implementation of appropriate surveillance strategies are crucial in managing this complex relationship. Furthermore, the findings of this study support a causative relationship between genetically predicted IBD and PBC risk, aligning with earlier studies conducted by Zhang and Zhao et al [ 75 , 76 ]. Disruption of intestinal permeability in IBD may lead to bacterial translocation, bile duct cell activation, and liver inflammation, ultimately contributing to the onset of PBC [ 77 ].…”

Inflammatory bowel disease and risk of autoimmune hepatitis: A univariable and multivariable Mendelian randomization study

“…The association between PSC and AIH is notably prevalent, accounting for approximately 63% of PSC cases in pediatric patients with IBD [41]. Recent MR studies have also supported a positive causal relationship between IBD and both PSC and primary biliary cholangitis, which aligns with our findings [42,43]. Some authors have suggested that patients with IBD associated with AIH had a more refractory disease course and a higher likelihood of requiring rectal resection [44][45][46].…”