The mediating role of primary sclerosing cholangitis in the association between ulcerative colitis and hepatobiliary cancer investigated through Mendelian randomization

This study explored the causal relationships among primary sclerosing cholangitis (PSC), ulcerative colitis (UC), and hepatobiliary cancer (HBC) by using bidirectional two-sample, two-step Mendelian randomization (MR) analysis. Genetic variants associated with PSC and UC from the FinnGen research database were used for instrumental variable-based analyses. Mediation analyses were conducted to examine the role of PSC and UC in HBC risk. The findings revealed a causal effect of genetic predisposition to UC on PSC risk (inverse-variance-weighted [IVW] analysis odds ratio [OR] 1.145, p < 0.001), whereas no reverse causality was observed. Although UC showed no direct causal effect on HBC risk, genetic susceptibility to PSC significantly increased the risk of HBC (IVW analysis OR = 1.855, p < 0.001). Mediation analysis further identified PSC as a significant mediator amplifying the causal effect of UC on HBC risk (effect size = 0.083). These results established a causal link between genetic susceptibility to UC and increased risk of PSC, and highlighted the critical role of PSC in mediating the impact of UC on HBC risk.