{"id":"8f88a2ba6e81","type":"article","url":"https://hartvaat.nl/2017/07/20/genetische-en-farmacologische-inactivatie-van-angptl3-en-cardiovasculaire-ziekte/","title":"Genetische en farmacologische inactivatie van ANGPTL3 en cardiovasculaire ziekte — NEJM","title_en":"Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.","category":"cholesterol","category_label":"Cholesterol","professions":["cardioloog","internist"],"tags":["cardiovasculaire-genetica","gepersonaliseerde-geneeskunde","lipoproteïne-a"],"journal":"The New England journal of medicine","doi":"10.1056/NEJMoa1612790","source_url":"https://doi.org/10.1056/NEJMoa1612790","authors":["Frederick E Dewey","Viktoria Gusarova","Richard L Dunbar","Colm O'Dushlaine","Claudia Schurmann","Omri Gottesman","Shane McCarthy","Cristopher V Van Hout","Shannon Bruse","Hayes M Dansky","Joseph B Leader","Michael F Murray","Marylyn D Ritchie","H Lester Kirchner","Lukas Habegger","Alex Lopez","John Penn","An Zhao","Weiping Shao","Neil Stahl","Andrew J Murphy","Sara Hamon","Aurelie Bouzelmat","Rick Zhang","Brad Shumel","Robert Pordy","Daniel Gipe","Gary A Herman","Wayne H H Sheu","I-Te Lee","Kae-Woei Liang","Xiuqing Guo","Jerome I Rotter","Yii-Der I Chen","William E Kraus","Svati H Shah","Scott Damrauer","Aeron Small","Daniel J Rader","Anders Berg Wulff","Børge G Nordestgaard","Anne Tybjærg-Hansen","Anita M van den Hoek","Hans M G Princen","David H Ledbetter","David J Carey","John D Overton","Jeffrey G Reid","William J Sasiela","Poulabi Banerjee","Alan R Shuldiner","Ingrid B Borecki","Tanya M Teslovich","George D Yancopoulos","Scott J Mellis","Jesper Gromada","Aris Baras"],"significance":8,"published":"2017-07-20","source_date":"2017-07-20","image":"","kennis":["https://hartvaat.nl/kennis/lipiden/lp-a-verhoogd/","https://hartvaat.nl/kennis/lipiden/lpa-meten-wanneer-waarom/"],"congress":"","summary_en":"This NEJM study showed that genetic loss-of-function variants in ANGPTL3 are associated with reduced plasma lipid levels and lower cardiovascular risk, providing the genetic foundation for pharmacological ANGPTL3 inhibition as a cardiovascular prevention strategy.","created":"2026-07-03T10:26:48Z","updated":"2026-07-03T13:26:06Z","licence":"Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.","body_markdown":"NEJM-studie die aantoont dat genetische inactivatie van ANGPTL3 geassocieerd is met verlaagd cardiovasculair risico. Onderbouwt ANGPTL3 als nieuw therapeutisch doelwit voor lipidenmodulatie.","abstract_original":"BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .)."}