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

Abstract

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.

Keywords: Mendelian randomization; causal relationship; hepatobiliary cancer; mediator; primary sclerosing cholangitis; ulcerative colitis.

Fig. 1

This Figure illustrates a diagram of the MR study. The study’s flowchart is structured upon three core assumptions. (I) Relevance to Exposure: The instrumental variables (IVs) must exhibit a statistically significant connection to the exposure under investigation (II) Independence from Confounding: The IVs should remain disconnected from any recognized confounding factors that could potentially modify the relationship between an exposure and its associated outcome. (III) Exclusion Restriction: The IVs should bear no direct influence on the outcomes; their impact is solely mediated by their effects on the exposure of interest.

Fig. 2

MR estimates derived from the fixed-effect IVW method, MR-Egger regression, weighted median method, weighted-mode method, simple-mode and random-effect IVW method to assess the causal effect between PSC and UC. (A) Results of forward MR and reverse MR analysis between PSC and UC. (B) Scatter plots showing the MR effect of each exposure on PSC. (C) Scatter plots showing the MR effect of each exposure on UC. PSC primary sclerosing cholangitis, UC ulcerative colitis.

Fig. 3

MR estimates derived from the fixed-effect IVW method, MR-Egger regression, weighted median method, weighted-mode method, simple-mode and random-effect IVW method to assess the causal effect of UC on HBC and PSC on HBC. (A) Results of MR analysis between liability to UC or PSC and the HBC risk. (B) Scatter plots showing the MR effect of each exposure on PSC. (C) Scatter plots showing the MR effect of each exposure on UC. UC ulcerative colitis, PSC primary sclerosing cholangitis, HBC hepatobiliary cancer.