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

• Published in: Scientific reports Vol. 14; no. 1; pp. 31433 - 8
• Main Authors: Wang, Fangming, Xiao, Junhui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.12.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/67/2195; 631/67/2322; 631/67/2324; Biliary Tract Neoplasms - epidemiology; Biliary Tract Neoplasms - etiology; Biliary Tract Neoplasms - genetics; causal relationship; Cholangitis; Cholangitis, Sclerosing - complications; Cholangitis, Sclerosing - genetics; Colitis, Ulcerative - complications; Colitis, Ulcerative - genetics; Genetic analysis; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; hepatobiliary cancer; Humanities and Social Sciences; Humans; Inflammatory bowel disease; Liver Neoplasms - genetics; mediator; Mendelian randomization; Mendelian Randomization Analysis; multidisciplinary; Polymorphism, Single Nucleotide; primary sclerosing cholangitis; Risk Factors; Science; Science (multidisciplinary); Ulcerative colitis; hepatobiliary cancer; ulcerative colitis; Mendelian randomization; causal relationship; mediator; primary sclerosing cholangitis
• DOI: 10.1038/s41598-024-83085-0
• ISSN: 2045-2322

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.