Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Frederick E Dewey; Viktoria Gusarova; Richard L Dunbar; Colm T 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

doi:10.1056/nejmoa1612790

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Frederick E Dewey, Viktoria Gusarova, Richard L Dunbar, Colm T 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

Department of Clinical Medicine

286 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 language	English
Journal	New England Journal of Medicine
Volume	377
Issue number	3
Pages (from-to)	211-221
ISSN	0028-4793
DOIs	https://doi.org/10.1056/nejmoa1612790
Publication status	Published - 20 Jul 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1056/nejmoa1612790

http://europepmc.org/articles/pmc5800308?pdf=renderLicence: Other

Cite this

Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C. T., Schurmann, C., Gottesman, O., McCarthy, S., Van Hout, C. V., Bruse, S., Dansky, H. M., Leader, J. B., Murray, M. F., Ritchie, M. D., Kirchner, H. L., Habegger, L., Lopez, A., Penn, J., Zhao, A., Shao, W., ... 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, FE, Gusarova, V, Dunbar, RL, O'Dushlaine, CT, 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, WH-H, Lee, I-T, Liang, K-W, Guo, X, Rotter, JI, Chen, YI, 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

@article{29445d9cd9e04ec5951ddf4f63fad072,

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.",

keywords = "Journal Article",

author = "Dewey, {Frederick E} and Viktoria Gusarova and Dunbar, {Richard L} and O'Dushlaine, {Colm T} 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 I-Te Lee and Kae-Woei Liang 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",

year = "2017",

month = jul,

day = "20",

doi = "10.1056/nejmoa1612790",

language = "English",

volume = "377",

pages = "211--221",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "3",

}

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 T

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 D

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.

KW - Journal Article

U2 - 10.1056/nejmoa1612790

DO - 10.1056/nejmoa1612790

M3 - Journal article

C2 - 28538136

SN - 0028-4793

VL - 377

SP - 211

EP - 221

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 3

ER -

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this