{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T02:58:55Z","timestamp":1789095535602,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background & Aims<\/jats:title>\n \n Lifelong\n APOB<\/jats:italic>\n gene inactivation lowers LDL\u2010C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long\u2010term cardiovascular protection and CLD risk in\n APOB<\/jats:italic>\n variant carriers has never been evaluated.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Using UK Biobank data, we analysed 241\n APOB<\/jats:italic>\n loss\u2010of\u2010function (LoF) carriers and 410\u2009721 non\u2010carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the\n PNPLA3<\/jats:italic>\n \u2010rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n APOB<\/jats:italic>\n carriers had ~35% lower LDL\u2010C and apoB levels, along with reduced total triglycerides and Lp(a) (all\n p<\/jats:italic>\n \u2009<\u20090.001). Baseline ALT and AST were higher in carriers than in non\u2010carriers (\n P<\/jats:italic>\n adj<\/jats:sub>\n \u2009=\u20093.6\u2009\u00d7\u200910\n \u22127<\/jats:sup>\n ), particularly among those with obesity (\n p<\/jats:italic>\n \u2009\u2264\u20090.003). The prevalence and incidence of CLD were consistently higher in carriers across all risk factor categories (\n p<\/jats:italic>\n \u2009\u2264\u20090.01), with the strongest association in those with diabetes and obesity over 15\u2009years of follow\u2010up (\n P<\/jats:italic>\n adj<\/jats:sub>\n \u2009=\u20090.03). In contrast,\n APOB<\/jats:italic>\n carriers as a whole had a 57% lower ASCVD risk (\n P<\/jats:italic>\n adj<\/jats:sub>\n \u2009\n =<\/jats:italic>\n \u20090.009), with a similar atheroprotective trend across all risk factor categories. This corresponded to an absolute risk reduction of 2.30 ASCVD events\/1000 person\u2010years (\n p<\/jats:italic>\n \u2009=\u20090.002) and an absolute increase of 3.48 CLD events\/1000 person\u2010years (\n p<\/jats:italic>\n \u2009=\u20090.003).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Long\u2010term exposure to low LDL\u2010C levels due to\n APOB<\/jats:italic>\n LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB\u2010targeting therapies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/liv.70515","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T10:04:16Z","timestamp":1768817056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Low Cholesterol due to\n APOB<\/i>\n Variants: Exploring the Balance Between Liver and Cardiovascular Risk"],"prefix":"10.1111","volume":"46","author":[{"given":"Alessia","family":"Di Costanzo","sequence":"first","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Pirona","sequence":"additional","affiliation":[{"name":"Istituto di Patologia Speciale Medica Catholic University of the Sacred Heart Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Buonaiuto","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics University of Tennessee Health Science Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Covino","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-1041","authenticated-orcid":false,"given":"Carlo","family":"Maiorca","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bini","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Tramontano","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilenia","family":"Minicocci","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Baratta","sequence":"additional","affiliation":[{"name":"Geriatric Unit, Department of Internal Medicine and Medical Specialties AOU Policlinico Umberto I Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenza","family":"Colonna","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics University of Tennessee Health Science Center Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allegra","family":"Via","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi Fanelli\u201d Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"D'Erasmo","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Arca","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.11.079"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpc.2024.100649"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108507"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-024-03700-9"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2022.5271"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1612790"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000663"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.19.11.2714"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0b013e3282ffd9f8"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.08.013"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.118.002376"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr509"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2017.05.007"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2021.100066"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.02.030"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3855"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31238"},{"key":"e_1_2_11_23_1","first-page":"92","volume-title":"Statsmodels: Econometric and Statistical Modeling With Python","author":"Seabold S.","year":"2010"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-151-5-200909010-00003"},{"key":"e_1_2_11_25_1","volume-title":"GeneReviews","author":"Burnett J. 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