Liver Steatosis‐Related Polygenic Risk Score Predicts Hepatocellular Carcinoma Risk After Hepatitis C Virus Eradication

BACKGROUND AND AIMS: Genetic predisposition to hepatic steatosis may increase hepatocellular carcinoma (HCC) risk after hepatitis C virus (HCV) eradication in cirrhotic patients; however, its impact on broader patient populations remains unexplored. We aimed to evaluate the association of steatosis-polygenic risk score (PRS) with HCC following direct-acting antiviral (DAA) therapy. METHODS: This retrospective cohort study utilised data from the Taiwan Precision Medicine Initiative, including adults treated with DAAs for HCV. Patients with treatment failure, hepatitis B virus co-infection, significant alcohol use, or HCC diagnosis prior to sustained virological response at 24 weeks were excluded. All participants underwent genotyping, with PRS-5 being used to quantify genetic risk. We evaluated the association between PRS-5 and the risk of incident HCC using restricted cubic spline analysis with Cox proportional hazards models. RESULTS: (aSHR 2.68, 95% CI 1.24-5.78; p = 0.012), and Fibrosis-4 index > 3.25 (aSHR 4.58, 95% CI 2.20-9.53; p < 0.001) were independently associated with HCC occurrence. Subgroup analysis supported the predictive value of PRS-5 in almost all patient subgroups, including Fibrosis-4 index < 3.25 and non-cirrhosis. CONCLUSIONS: PRS-5 is independently associated with increased HCC risk after HCV eradication, supporting its role in personalised HCC surveillance strategies.