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

ABSTRACT 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 The cohort included 420 patients (median age 67.0 years; 46.9% male). The 5‐year cumulative incidence of HCC in PRS‐5 ≥ 0.66 group was higher than PRS‐5 24 kg/m 2 (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.