@article{75f3666022b14ee8929a45ff5d57415c,
title = "Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease",
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.",
author = "Dewey, {Frederick E.} and Viktoria Gusarova and Dunbar, {Richard L.} and Colm O'Dushlaine and Claudia Schurmann and Omri Gottesman and Shane McCarthy and {Van Hout}, {Cristopher V.} and Shannon Bruse and Dansky, {Hayes M.} and Leader, {Joseph B.} and Murray, {Michael F.} and Ritchie, {Marylyn D.} and Kirchner, {H. Lester} and Lukas Habegger and Alex Lopez and John Penn and An Zhao and Weiping Shao and Neil Stahl and Murphy, {Andrew J.} and Sara Hamon and Aurelie Bouzelmat and Rick Zhang and Brad Shumel and Robert Pordy and Daniel Gipe and Herman, {Gary A.} and Sheu, {Wayne H.H.} and Lee, {I. Te} and Liang, {Kae Woei} and Xiuqing Guo and Rotter, {Jerome I.} and Chen, {Yii Der I.} and Kraus, {William E.} and Shah, {Svati H.} and Scott Damrauer and Aeron Small and Rader, {Daniel J.} and Wulff, {Anders Berg} and Nordestgaard, {B{\o}rge G.} and Anne Tybj{\ae}rg-Hansen and {Van Den Hoek}, {Anita M.} and Princen, {Hans M.G.} and Ledbetter, {David H.} and Carey, {David J.} and Overton, {John D.} and Reid, {Jeffrey G.} and Sasiela, {William J.} and Poulabi Banerjee and Shuldiner, {Alan R.} and Borecki, {Ingrid B.} and Teslovich, {Tanya M.} and Yancopoulos, {George D.} and Mellis, {Scott J.} and Jesper Gromada and Aris Baras",
note = "Funding Information: The DiscovEHR study was partially funded by Regeneron Pharmaceuticals. The evinacumab clinical trial was funded by Regeneron Pharmaceuticals. The Penn Medicine BioBank was funded by the Perelman School of Medicine and a gift from the Smilow family. Dr. Shah (Duke Catheterization Genetics biorepository) was supported by a grant (R01-HL127009-01A1) from the National Institutes of Health. The TAICHI study was supported by grants from the National Health Research Institutes, Taiwan (PH-099-PP-03, PH-100-PP-03, and PH-101-PP-03); the National Science Council, Taiwan (NSC 101-2314-B-075A-006-MY3, MOST 104-2314-B-075A-006-MY3, MOST 104-2314-B-075A-007, and MOST 105-2314-B-075A-003); and the Taichung Veterans General Hospital, Taiwan (TCVGH-1020101C, TCVGH-1020102D, TCVGH-1023102B, TCVGH-1023107D, TCVGH-1030101C, TCVGH- 1030105D, TCVGH-1033503C, TCVGH-1033102B, TCVGH-1033108D, TCVGH-1040101C, TCVGH-1040102D, TCVGH-1043504C, and TCVGH-1043104B); it was also supported in part by the National Center for Advancing Translational Sciences (CTSI grant UL1TR001881). Publisher Copyright: Copyright {\textcopyright} 2017 Massachusetts Medical Society. All rights reserved.",
year = "2017",
month = jul,
day = "20",
doi = "10.1056/NEJMoa1612790",
language = "English (US)",
volume = "377",
pages = "211--221",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "3",
}