Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

Autor:	Gobeil É; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Bourgault J; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Mitchell PL; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Houessou U; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Gagnon E; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Girard A; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Paulin A; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Manikpurage HD; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Côté V; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Couture C; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada., Marceau S; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Bossé Y; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada., Thériault S; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, Canada., Mathieu P; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; Department of Surgery, Faculty of Medicine, Université Laval, Québec, Canada., Vohl MC; School of Nutrition, Université Laval, Québec, Canada.; Centre Nutrition, santé et société, Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, Canada., Tchernof A; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; School of Nutrition, Université Laval, Québec, Canada., Arsenault BJ; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.; Department of Medicine, Faculty of Medicine, Université Laval, 2325 Rue de l'Université, Québec, QC G1V 0A6, Canada.
Jazyk:	angličtina
Zdroj:	European heart journal [Eur Heart J] 2024 Mar 01; Vol. 45 (9), pp. 707-721.
DOI:	10.1093/eurheartj/ehad845
Abstrakt:	Background and Aims: 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. Methods: 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. Results: 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 [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 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). Conclusions: 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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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