Carriage of rare APOB variants predisposes to severe steatotic liver disease and hepatocellular carcinoma.
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Mureddu Matteo, Pelusi Serena, Jamialahmadi Oveis, Vujkovic Marijana, Miano Lorenzo, Eidgah Torghabehei Hadi, Ronzoni Luisa, Malvestiti Francesco, Saracino Marco, Periti Giulia, Moretti Vittoria, Teerlink Craig C, Lynch Julie A, Tsao Philip S, Johnson Josephine P, La Mura Vincenzo, Dilena Robertino, Alqahtani Saleh A, Cherubini Alessandro, EPIDEMIC Study Investigators, Million Veteran Program, Russo Francesco Paolo, D'Ambrosio Roberta, Fraquelli Mirella, Petta Salvatore, Miele Luca, Vespasiani-Gentilucci Umberto, Bugianesi Elisabetta, Mancina Rosellina M, Parini Paolo, Prati Daniele, Chang Kyong-Mi, Schneider Carolin V, Romeo Stefano, Valenti Luca Vc
Аннотация
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.