{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:30:56Z","timestamp":1790188256730,"version":"4.1.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012727","name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012727","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Genotype-Tissue Expression"},{"name":"GTEx"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de recherche du Qu\u00e9bec: Sant\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pathobiology of Calcific Aortic Valve Disease"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background and Aims<\/jats:title>\n                  <jats:p>RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [\u22120.37 (interquartile range 0.41) mmol\/L] had slightly lower apoB levels (\u22120.06 \u00b1 0.32 g\/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and\/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehad845","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T11:33:03Z","timestamp":1705750383000},"page":"707-721","source":"Crossref","is-referenced-by-count":35,"title":["Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk"],"prefix":"10.1093","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-0731","authenticated-orcid":false,"given":"\u00c9milie","family":"Gobeil","sequence":"first","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec\u2014Universit\u00e9 Laval , 2725 chemin Ste-Foy, Qu\u00e9bec, QC G1V 4G5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-353X","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Bourgault","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec\u2014Universit\u00e9 Laval , 2725 chemin Ste-Foy, Qu\u00e9bec, QC G1V 4G5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-1047","authenticated-orcid":false,"given":"Patricia L","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec\u2014Universit\u00e9 Laval , 2725 chemin Ste-Foy, Qu\u00e9bec, QC G1V 4G5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8716-3007","authenticated-orcid":false,"given":"Ursula","family":"Houessou","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec\u2014Universit\u00e9 Laval , 2725 chemin Ste-Foy, Qu\u00e9bec, QC G1V 4G5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7483-1371","authenticated-orcid":false,"given":"Eloi","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec\u2014Universit\u00e9 Laval , 2725 chemin Ste-Foy, Qu\u00e9bec, QC G1V 4G5 , 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