{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:22:05Z","timestamp":1790788925301,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T00:00:00Z","timestamp":1746835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"the Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Foundation of the IUCPQ"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>RNA interference therapies targeting liver expression of the gene proprotein convertase subtilisin\/kexin type 9 (PCSK9) lower LDL-cholesterol (LDL-C) and apolipoprotein B (apoB) levels. As opposed to monoclonal antibodies, which neutralise PCSK9 circulating protein, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used genetic variants in the PCSK9 locus influencing PCSK9 function or gene expression in the liver to determine whether antibodies against PCSK9 and RNA interference therapies could have comparable effects on ASCVD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We performed genome-wide genotyping and RNA sequencing of 504 human liver sample and identified a genetic variant (rs472495) explaining 5.6% of liver PCSK9 gene expression to mimic lifelong RNA interference of PCSK9. We used the PCSK9 R46L variant, known to alter PCSK9 function, to model antibody-based PCSK9 inhibition. For each standard deviation decrease in apoB levels, both variants were similarly associated with coronary artery disease risk: (odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.31\u20130.51, P = 3.7e\u201313 for rs472495 which affects liver PCSK9 expression) and (OR = 0.48, 95% CI: 0.43\u20130.55, P = 1.3e\u201328 for R46L which affects protein levels). Comparable effects of these two genetic inhibition approaches were observed for aortic stenosis, heart failure, ischemic stroke, Type 2 diabetes and glycemic traits as well as non-alcoholic fatty liver disease and liver enzymes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>For a given reduction in apoB levels, genetically predicted reductions in PCSK9 function (mimicking PCSK9 neutralizing antibodies) and liver PCSK9 gene expression levels (mimicking PCSK9 RNA interference) were comparably associated with a lower risk of coronary artery disease. These genetic data suggest that LDL-C\/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf078","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T17:23:59Z","timestamp":1746897839000},"page":"1066-1075","source":"Crossref","is-referenced-by-count":4,"title":["RNA interference versus antibody-based PCSK9 inhibition for the prevention of cardiovascular disease: a drug-target Mendelian randomization study"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7483-1371","authenticated-orcid":false,"given":"Eloi","family":"Gagnon","sequence":"first","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipender","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London , London ,","place":["UK"]}],"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 - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-0731","authenticated-orcid":false,"given":"\u00c9milie","family":"Gobeil","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["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 - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8219-9118","authenticated-orcid":false,"given":"Arnaud","family":"Girard","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1224-9538","authenticated-orcid":false,"given":"Audrey","family":"Paulin","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-8780","authenticated-orcid":false,"given":"Christian","family":"Couture","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3067-3711","authenticated-orcid":false,"given":"Yohan","family":"Boss\u00e9","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]},{"name":"Department of Molecular Medicine, Faculty of Medicine, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-8307","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Th\u00e9riault","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]},{"name":"Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3805-2004","authenticated-orcid":false,"given":"Patrick","family":"Mathieu","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]},{"name":"Department of Surgery, Faculty of Medicine, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7017-5848","authenticated-orcid":false,"given":"Marie-Claude","family":"Vohl","sequence":"additional","affiliation":[{"name":"School of Nutrition, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]},{"name":"Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9, Institut sur la nutrition et les aliments fonctionnels, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2587-1000","authenticated-orcid":false,"given":"Andr\u00e9","family":"Tchernof","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Qu\u00e9bec, QC , G1V 4G5","place":["Canada"]},{"name":"School of Nutrition, Universit\u00e9 Laval , Qu\u00e9bec, QC ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kausik K","family":"Ray","sequence":"additional","affiliation":[{"name":"Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J P","family":"Kastelein","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2240-8456","authenticated-orcid":false,"given":"Benoit J","family":"Arsenault","sequence":"additional","affiliation":[{"name":"Centre de recherche de l\u2019Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval , Y-3106, Pavillon Marguerite 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