Carriage of rare APOB variants predisposes to severe steatotic liver disease and hepatocellular carcinoma

Clinical Snapshot

Key Findings

• P Value: P = 0.002 for advanced MASLD association, P < 0.05 for other outcomes

• Effect Size: OR 13.8 for advanced MASLD, OR 1.82 for cirrhosis, OR 3.53 for HCC

• Primary Outcome: Advanced MASLD risk associated with rare APOB variants

• Nnt Or Sensitivity: Variants present in ~2% of advanced MASLD cases vs 0.4% controls, suggesting potential screening utility in high-risk populations

• Confidence Interval: Advanced MASLD: 95% CI 2.7-70.7; Cirrhosis: 95% CI 1.33-2.49; HCC: 95% CI 2.09-5.98

Clinical Application

Genetic testing feasible but currently expensive for routine screening. May be valuable for risk stratification in specialist hepatology practice Relevant to Australian practice given high MASLD prevalence. Could inform PBS-funded genetic testing criteria for high-risk patients. Aligns with RACGP guidelines for personalised medicine approaches to chronic disease management Adults with MASLD, particularly those with family history or early-onset severe disease, patients undergoing HCC surveillance

Abstract

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH.

References

1. 1.Mureddu, M., Pelusi, S., Jamialahmadi, O., Vujkovic, M., Miano, L., Eidgah Torghabehei, H., Ronzoni, L., Malvestiti, F., Saracino, M., Periti, G., Moretti, V., Teerlink, C. C., Lynch, J. A., Tsao, P. S., Johnson, J. P., La Mura, V., Dilena, R., Alqahtani, S. A., Cherubini, A., Russo, F. P., D'Ambrosio, R., Fraquelli, M., Petta, S., Miele, L., Vespasiani-Gentilucci, U., Bugianesi, E., Mancina, R. M., Parini, P., Prati, D., Chang, K. M., Schneider, C. V., Romeo, S., & Valenti, L. V. (2026). Carriage of rare APOB variants predisposes to severe steatotic liver disease and hepatocellular carcinoma. The Journal of Clinical Investigation. https://doi.org/10.1093/bioinformatics/bth457