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] 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 < 0.66 group (23.97%, 95% confidence interval (CI) 7.15%-40.79% vs. 8.89%, 95% CI 5.56%-12.23%; p = 0.014). In multivariable regression, PRS-5 ≥ 0.66 (aSHR 3.59, 95% CI 1.69-7.63; p < 0.001), body weight index > 24 kg/m (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.