Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease

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 StahlAndrew 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

Research output: Contribution to journalArticlepeer-review

231 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)211-221
Number of pages11
JournalNew England Journal of Medicine
Volume377
Issue number3
DOIs
StatePublished - Jul 20 2017

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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