{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:08:31Z","timestamp":1787861311079,"version":"build-2784847793"},"reference-count":39,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":64,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["Ricerca Finalizzata 2021 RF-2021-12373889,Ricerca Finalizzata PNRR 2022 \u201cRATIONAL\u201d PNRR-MAD-2022-12375656"],"award-info":[{"award-number":["Ricerca Finalizzata 2021 RF-2021-12373889,Ricerca Finalizzata PNRR 2022 \u201cRATIONAL\u201d PNRR-MAD-2022-12375656"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"crossref","award":["H2020-ICT-2018-20\/H2020-ICT-2020-2 programme \u201cPhotonics\u201d under grant agreement No. 101016726 - REVEAL,HORIZON-MISS-2021-CANCER-02-03 programme \u201cGenial\u201d under grant agreement \u201c101096312\u201d"],"award-info":[{"award-number":["H2020-ICT-2018-20\/H2020-ICT-2020-2 programme \u201cPhotonics\u201d under grant agreement No. 101016726 - REVEAL,HORIZON-MISS-2021-CANCER-02-03 programme \u201cGenial\u201d under grant agreement \u201c101096312\u201d"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Ministry of Research","award":["NRR \u2013 M4 - C2 \u201cNational Center for Gene Therapy"],"award-info":[{"award-number":["NRR \u2013 M4 - C2 \u201cNational Center for Gene Therapy"]}]},{"name":"Italian Ministry of Research","award":["Drugs based on RNA Technology\u201d CN3,Spoke 4 \u201cASSET\u201d"],"award-info":[{"award-number":["Drugs based on RNA Technology\u201d CN3,Spoke 4 \u201cASSET\u201d"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,15]]},"abstract":"\n BACKGROUND<\/jats:title>\n \n Metabolic dysfunction\u2013associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (\n APOB<\/jats:italic>\n ) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n We investigated\n APOB<\/jats:italic>\n rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (\n n<\/jats:italic>\n = 510 and 261, respectively), a family-based study (\n n<\/jats:italic>\n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (\n n<\/jats:italic>\n = 94,885), and the UK Biobank (UKBB) (\n n<\/jats:italic>\n = 417,657).\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n In the clinical cohort,\n APOB<\/jats:italic>\n variants were enriched in people with advanced MASLD (OR 13\n .<\/jats:italic>\n 8, 95% CI: 2\n .<\/jats:italic>\n 7\u201370\n .<\/jats:italic>\n 7,\n P<\/jats:italic>\n = 0\n .<\/jats:italic>\n 002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (\n P<\/jats:italic>\n < 0\n .<\/jats:italic>\n 05). In the family study,\n APOB<\/jats:italic>\n variants segregated with hepatic steatosis and fibrosis (\n P<\/jats:italic>\n < 0\n .<\/jats:italic>\n 05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1\n .<\/jats:italic>\n 82, 95% CI: 1\n .<\/jats:italic>\n 33\u20132\n .<\/jats:italic>\n 49 and 3\n .<\/jats:italic>\n 53, 95% CI: 2\n .<\/jats:italic>\n 09\u20135\n .<\/jats:italic>\n 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 (\n P<\/jats:italic>\n < 0\n .<\/jats:italic>\n 05). The variants affected cirrhosis risk similarly, but ApoB48\/100 had a larger effect on HCC (\n P<\/jats:italic>\n < 0\n .<\/jats:italic>\n 05).\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n \n Rare\n APOB<\/jats:italic>\n 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\n APOB<\/jats:italic>\n genotyping may enhance MASLD risk stratification and patient identification.\n <\/jats:p>\n <\/jats:sec>\n \n FUNDING<\/jats:title>\n European Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH.<\/jats:p>\n <\/jats:sec>","DOI":"10.1172\/jci201762","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:00:15Z","timestamp":1770742815000},"source":"Crossref","is-referenced-by-count":4,"title":["Carriage of rare APOB variants predisposes to severe steatotic liver disease and hepatocellular carcinoma"],"prefix":"10.1172","volume":"136","author":[{"given":"Matteo","family":"Mureddu","sequence":"first","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Pelusi","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oveis","family":"Jamialahmadi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijana","family":"Vujkovic","sequence":"additional","affiliation":[{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA."},{"name":"University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Miano","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy."},{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Eidgah Torghabehei","sequence":"additional","affiliation":[{"name":"Scientific Direction, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Ronzoni","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Malvestiti","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Saracino","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Periti","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Moretti","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Milano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig C.","family":"Teerlink","sequence":"additional","affiliation":[{"name":"VA Salt Lake City and"},{"name":"University of Utah School of Medicine, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Lynch","sequence":"additional","affiliation":[{"name":"VA Salt Lake City and"},{"name":"University of Utah School of Medicine, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Tsao","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System and Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine P.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Corporal Michael J. 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