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

Background: 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. Methods: We investigated APOB rare variants in a case-control cohort of people with advanced MASLD vs. healthy controls (n = 510/261), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program cohort (MVP, n = 94,885) and the UK Biobank (UKBB, n = 417,657). Results: In the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% c.i. 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 of 1.82, 95% c.i. 1.33-2.49 and 3.53, 95% c.i. 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a three-fold greater impact on hepatic lipid metabolism compared to those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). Variants affected cirrhosis risk similarly, but ApoB48/100 had a larger impact on hepatocellular carcinoma (P < 0.05). Conclusions: Rare APOB variants predispose 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 case identification. Funding: European Union, Italian Ministry of Health, Swedish Research Council, Veteran health administration, NIH.