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 Deriggi Ritchie, H. Lester Kirchner, Lukas Habegger, Alex Lopez, John Penn, An Zhao, Weiping Shao, Neil Stahl & 37 others 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

Research output: Contribution to journalArticle

138 Citations (Scopus)

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

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Angiopoietins
Cardiovascular Diseases
LDL Cholesterol
Triglycerides
Genes
HDL Cholesterol
Coronary Artery Disease
Lipids
Medical Genetics
Exons
Fasting
Healthy Volunteers
Odds Ratio
Monoclonal Antibodies
Placebos
Confidence Intervals
Antibodies
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C., Schurmann, C., Gottesman, O., ... Baras, A. (2017). Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. New England Journal of Medicine, 377(3), 211-221. https://doi.org/10.1056/NEJMoa1612790
Dewey, Frederick E. ; Gusarova, Viktoria ; Dunbar, Richard L. ; O'Dushlaine, Colm ; Schurmann, Claudia ; Gottesman, Omri ; McCarthy, Shane ; Van Hout, Cristopher V. ; Bruse, Shannon ; Dansky, Hayes M. ; Leader, Joseph B. ; Murray, Michael F. ; Ritchie, Marylyn Deriggi ; Kirchner, H. Lester ; Habegger, Lukas ; Lopez, Alex ; Penn, John ; Zhao, An ; Shao, Weiping ; Stahl, Neil ; Murphy, Andrew J. ; Hamon, Sara ; Bouzelmat, Aurelie ; Zhang, Rick ; Shumel, Brad ; Pordy, Robert ; Gipe, Daniel ; Herman, Gary A. ; Sheu, Wayne H.H. ; Lee, I. Te ; Liang, Kae Woei ; Guo, Xiuqing ; Rotter, Jerome I. ; Chen, Yii Der I. ; Kraus, William E. ; Shah, Svati H. ; Damrauer, Scott ; Small, Aeron ; Rader, Daniel J. ; Wulff, Anders Berg ; Nordestgaard, Børge G. ; Tybjærg-Hansen, Anne ; Van Den Hoek, Anita M. ; Princen, Hans M.G. ; Ledbetter, David H. ; Carey, David J. ; Overton, John D. ; Reid, Jeffrey G. ; Sasiela, William J. ; Banerjee, Poulabi ; Shuldiner, Alan R. ; Borecki, Ingrid B. ; Teslovich, Tanya M. ; Yancopoulos, George D. ; Mellis, Scott J. ; Gromada, Jesper ; Baras, Aris. / Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. In: New England Journal of Medicine. 2017 ; Vol. 377, No. 3. pp. 211-221.
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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 Deriggi} 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",
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Dewey, FE, Gusarova, V, Dunbar, RL, O'Dushlaine, C, Schurmann, C, Gottesman, O, McCarthy, S, Van Hout, CV, Bruse, S, Dansky, HM, Leader, JB, Murray, MF, Ritchie, MD, Kirchner, HL, Habegger, L, Lopez, A, Penn, J, Zhao, A, Shao, W, Stahl, N, Murphy, AJ, Hamon, S, Bouzelmat, A, Zhang, R, Shumel, B, Pordy, R, Gipe, D, Herman, GA, Sheu, WHH, Lee, IT, Liang, KW, Guo, X, Rotter, JI, Chen, YDI, Kraus, WE, Shah, SH, Damrauer, S, Small, A, Rader, DJ, Wulff, AB, Nordestgaard, BG, Tybjærg-Hansen, A, Van Den Hoek, AM, Princen, HMG, Ledbetter, DH, Carey, DJ, Overton, JD, Reid, JG, Sasiela, WJ, Banerjee, P, Shuldiner, AR, Borecki, IB, Teslovich, TM, Yancopoulos, GD, Mellis, SJ, Gromada, J & Baras, A 2017, 'Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease', New England Journal of Medicine, vol. 377, no. 3, pp. 211-221. https://doi.org/10.1056/NEJMoa1612790

Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. / Dewey, Frederick E.; Gusarova, Viktoria; Dunbar, Richard L.; O'Dushlaine, Colm; Schurmann, Claudia; Gottesman, Omri; McCarthy, Shane; Van Hout, Cristopher V.; Bruse, Shannon; Dansky, Hayes M.; Leader, Joseph B.; Murray, Michael F.; Ritchie, Marylyn Deriggi; Kirchner, H. Lester; Habegger, Lukas; Lopez, Alex; Penn, John; Zhao, An; Shao, Weiping; Stahl, Neil; Murphy, Andrew J.; Hamon, Sara; Bouzelmat, Aurelie; Zhang, Rick; Shumel, Brad; Pordy, Robert; Gipe, Daniel; Herman, Gary A.; Sheu, Wayne H.H.; Lee, I. Te; Liang, Kae Woei; Guo, Xiuqing; Rotter, Jerome I.; Chen, Yii Der I.; Kraus, William E.; Shah, Svati H.; Damrauer, Scott; Small, Aeron; Rader, Daniel J.; Wulff, Anders Berg; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Van Den Hoek, Anita M.; Princen, Hans M.G.; Ledbetter, David H.; Carey, David J.; Overton, John D.; Reid, Jeffrey G.; Sasiela, William J.; Banerjee, Poulabi; Shuldiner, Alan R.; Borecki, Ingrid B.; Teslovich, Tanya M.; Yancopoulos, George D.; Mellis, Scott J.; Gromada, Jesper; Baras, Aris.

In: New England Journal of Medicine, Vol. 377, No. 3, 20.07.2017, p. 211-221.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease

AU - Dewey, Frederick E.

AU - Gusarova, Viktoria

AU - Dunbar, Richard L.

AU - O'Dushlaine, Colm

AU - Schurmann, Claudia

AU - Gottesman, Omri

AU - McCarthy, Shane

AU - Van Hout, Cristopher V.

AU - Bruse, Shannon

AU - Dansky, Hayes M.

AU - Leader, Joseph B.

AU - Murray, Michael F.

AU - Ritchie, Marylyn Deriggi

AU - Kirchner, H. Lester

AU - Habegger, Lukas

AU - Lopez, Alex

AU - Penn, John

AU - Zhao, An

AU - Shao, Weiping

AU - Stahl, Neil

AU - Murphy, Andrew J.

AU - Hamon, Sara

AU - Bouzelmat, Aurelie

AU - Zhang, Rick

AU - Shumel, Brad

AU - Pordy, Robert

AU - Gipe, Daniel

AU - Herman, Gary A.

AU - Sheu, Wayne H.H.

AU - Lee, I. Te

AU - Liang, Kae Woei

AU - Guo, Xiuqing

AU - Rotter, Jerome I.

AU - Chen, Yii Der I.

AU - Kraus, William E.

AU - Shah, Svati H.

AU - Damrauer, Scott

AU - Small, Aeron

AU - Rader, Daniel J.

AU - Wulff, Anders Berg

AU - Nordestgaard, Børge G.

AU - Tybjærg-Hansen, Anne

AU - Van Den Hoek, Anita M.

AU - Princen, Hans M.G.

AU - Ledbetter, David H.

AU - Carey, David J.

AU - Overton, John D.

AU - Reid, Jeffrey G.

AU - Sasiela, William J.

AU - Banerjee, Poulabi

AU - Shuldiner, Alan R.

AU - Borecki, Ingrid B.

AU - Teslovich, Tanya M.

AU - Yancopoulos, George D.

AU - Mellis, Scott J.

AU - Gromada, Jesper

AU - Baras, Aris

PY - 2017/7/20

Y1 - 2017/7/20

N2 - 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.

AB - 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.

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DO - 10.1056/NEJMoa1612790

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Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. New England Journal of Medicine. 2017 Jul 20;377(3):211-221. https://doi.org/10.1056/NEJMoa1612790