Integrated Genetic Information of Metabolic Dysfunction-Associated Steatotic Liver Disease-Related Traits Improves Hepatocellular Carcinoma Risk Stratification and Screening

PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of hepatocellular carcinoma (HCC), yet current screening strategies overlook the genetic complexity of MASLD. We hypothesized that capturing this complexity through a multitrait polygenic approach could improve HCC prevention. METHODS: Using genome-wide association data for 10 MASLD-related traits in individuals of European ancestry, we constructed a meta-polygenic risk score (metaPRS) in the UK Biobank. We evaluated its performance in HCC prediction and its utility in stratified screening. Risk advancement period (RAP) analysis estimated how much earlier individuals in different genetic risk groups reach comparable risk levels. RESULTS: The metaPRS that incorporated genome-wide variants achieved a C-statistic of 0.686 for HCC prediction, outperforming existing PRSs. Individuals in the top 20% of genetic risk had a 5.33-fold higher HCC risk than those in the bottom 20%. RAP analysis showed that high-risk individuals reached the HCC risk threshold 11.91 years earlier than the intermediate group, whereas low-risk individuals reached it 5.49 years later, suggesting a shift in recommended screening age from 65 to 43 years. Genetic stratification by the metaPRS also improved the predictive performance of noninvasive fibrosis scores (eg, Forns score). Combining high genetic risk with an elevated Forns score yielded a 10-year HCC risk of 2.68%, compared with 0.01% in the lowest-risk group-reducing the number needed to screen from 7,918 to 27. CONCLUSION: The MASLD-related metaPRS supports effective population risk stratification and enables a layered HCC screening strategy combining genetic risk profiling with targeted clinical assessment.