Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

被引：657

作者：

Dewey, F. E. ^{[1
]}

Gusarova, V. ^{[2
]}

Dunbar, R. L. ^{[3
]}

O'Dushlaine, C. ^{[1
]}

Schurmann, C. ^{[1
]}

Gottesman, O. ^{[1
]}

McCarthy, S. ^{[1
]}

Van Hout, C. V. ^{[1
]}

Bruse, S. ^{[1
]}

Dansky, H. M. ^{[2
]}

Leader, J. B. ^{[6
,7
]}

Murray, M. F. ^{[6
,7
]}

Ritchie, M. D. ^{[6
,7
]}

Kirchner, H. L. ^{[6
,7
]}

Habegger, L. ^{[1
]}

Lopez, A. ^{[1
]}

Penn, J. ^{[1
]}

Zhao, A. ^{[2
]}

Shao, W. ^{[2
]}

Stahl, N. ^{[1
,2
]}

Murphy, A. J. ^{[1
,2
]}

Hamon, S. ^{[2
]}

Bouzelmat, A. ^{[2
]}

Zhang, R. ^{[2
]}

Shumel, B. ^{[2
]}

Pordy, R. ^{[2
]}

Gipe, D. ^{[2
]}

Herman, G. A. ^{[2
]}

Sheu, W. H. H. ^{[8
,10
,13
,14
]}

Lee, I-T. ^{[8
,11
,13
]}

Liang, K. -W. ^{[9
,12
,13
]}

Guo, X. ^{[15
,16
]}

Rotter, J. I. ^{[15
,16
]}

Chen, Y. -D. I. ^{[15
,16
]}

Kraus, W. E. ^{[17
]}

Shah, S. H. ^{[17
]}

Damrauer, S. ^{[4
]}

Small, A. ^{[5
]}

Rader, D. J. ^{[5
]}

Wulff, A. B. ^{[18
]}

Nordestgaard, B. G. ^{[18
,19
,20
,21
,22
,23
]}

Tybjaerg-Hansen, A. ^{[18
,19
,21
,22
,23
]}

van den Hoek, A. M. ^{[24
]}

Princen, H. M. G. ^{[24
]}

Ledbetter, D. H. ^{[6
,7
]}

Carey, D. J. ^{[6
,7
]}

Overton, J. D. ^{[1
]}

Reid, J. G. ^{[1
]}

Sasiela, W. J. ^{[2
]}

Banerjee, P. ^{[2
]}

机构：

[1] Regeneron Genet Ctr, Tarrytown, NY USA

[2] Regeneron Pharmaceut, Tarrytown, NY USA

[3] Univ Penn, Div Translat Med & Human, Dept Med, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Genet & Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Geisinger Hlth Syst, Danville, PA USA

[8] Natl Chung Hsing Univ, Div Endocrinol & Metab, Dept Internal Med, Taichung, Taiwan

[9] Natl Chung Hsing Univ, Cardiovasc Ctr, Taichung, Taiwan

[10] Natl Chung Hsing Univ, Inst Med Technol, Taichung Vet Gen Hosp, Taichung, Taiwan

[11] Chung Shan Med Univ, Sch Med, Taichung, Taiwan

[12] China Med Univ, Dept Med, Taichung, Taiwan

[13] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan

[14] Natl Def Med Ctr, Sch Med, Taipei, Taiwan

[15] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA

[16] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA

[17] Duke Univ, Sch Med, Div Cardiol, Dept Med,Mol Physiol Inst, Durham, NC USA

[18] Univ Copenhagen, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark

[19] Univ Copenhagen, Gen Populat Study, Copenhagen, Denmark

[20] Univ Copenhagen, Dept Clin Biochem, Copenhagen, Denmark

[21] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen, Denmark

[22] Univ Copenhagen, Copenhagen City Heart Study, Frederiksberg Hosp, Copenhagen Univ Hosp, Copenhagen, Denmark

[23] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[24] Gaubius Lab, TNO Metab Hlth Res, Leiden, Netherlands

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2017年 / 377卷 / 03期

关键词：

FAMILIAL COMBINED HYPOLIPIDEMIA; CORONARY-ARTERY-DISEASE; LIPOPROTEIN-LIPASE GENE; HEART-DISEASE; IMMUNOGLOBULIN GENES; REMNANT CHOLESTEROL; TRANSGENIC MICE; PLASMA-LIPIDS; RISK; ATHEROSCLEROSIS;

D O I：

10.1056/NEJMoa1612790

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.)

引用

页码：211 / 221

页数：11

共 38 条

[1] A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice [J].

Ando, Y ;

Shimizugawa, T ;

Takeshita, S ;

Ono, M ;

Shimamura, M ;

Koishi, R ;

Furukawa, H .

JOURNAL OF LIPID RESEARCH, 2003, 44 (06) :1216-1223

[2] Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium [J].

Assimes, Themistocles L. ;

Lee, I. -T. ;

Juang, Jyh-Ming ;

Guo, Xiuqing ;

Wang, Tzung-Dau ;

Kim, Eric T. ;

Lee, Wen-Jane ;

Absher, Devin ;

Chiu, Yen-Feng ;

Hsu, Chih-Cheng ;

Chuang, Lee-Ming ;

Quertermous, Thomas ;

Hsiung, Chao A. ;

Rotter, Jerome I. ;

Sheu, Wayne H. -H. ;

Chen, Yii-Der Ida ;

Taylor, Kent D. .

PLOS ONE, 2016, 11 (03)

[3] The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research [J].

Carey, David J. ;

Fetterolf, Samantha N. ;

Davis, Daniel ;

Faucett, William A. ;

Kirchner, H. Lester ;

Mirshahi, Uyenlinh ;

Murray, Michael F. ;

Smelser, Diane T. ;

Gerhard, Glenn S. ;

Ledbetter, David H. .

GENETICS IN MEDICINE, 2016, 18 (09) :906-913

[4] Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease [J].

Dewey, Frederick F. ;

Gusarova, Viktoria ;

O'Dushlaine, Colm ;

Gottesman, Omri ;

Trejos, Jesus ;

Hunt, Charleen ;

Van Hout, Cristopher V. ;

Habegger, Lukas ;

Buckler, David ;

Lai, Ka-Man V. ;

Leader, Joseph B. ;

Murray, Michael F. ;

Ritchie, Marylyn D. ;

Kirchner, H. Lester ;

Ledbetter, David H. ;

Penn, John ;

Lopez, Alexander ;

Borecki, Ingrid B. ;

Overton, John D. ;

Reid, Jeffrey G. ;

Carey, David J. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Baras, Aris ;

Gromada, Jesper ;

Shuldiner, Alan R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (12) :1123-1133

[5] Variation in ANGPTL4 and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study [J].

Folsom, Aaron R. ;

Peacock, James M. ;

Demerath, Ellen ;

Boerwinkle, Eric .

METABOLISM-CLINICAL AND EXPERIMENTAL, 2008, 57 (11) :1591-1596

[6] ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys [J].

Gusarova, Viktoria ;

Alexa, Corey A. ;

Wang, Yan ;

Rafique, Ashique ;

Kim, Jee Hae ;

Buckler, David ;

Mintah, Ivory J. ;

Shihanian, Lisa M. ;

Cohen, Jonathan C. ;

Hobbs, Helen H. ;

Xin, Yurong ;

Valenzuela, David M. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Gromada, Jesper .

JOURNAL OF LIPID RESEARCH, 2015, 56 (07) :1308-1317

[7] A solution to the problem of separation in logistic regression [J].

Heinze, G ;

Schemper, M .

STATISTICS IN MEDICINE, 2002, 21 (16) :2409-2419

[8] Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease [J].

Helgadottir, Anna ;

Gretarsdottir, Solveig ;

Thorleifsson, Gudmar ;

Hjartarson, Eirikur ;

Sigurdsson, Asgeir ;

Magnusdottir, Audur ;

Jonasdottir, Aslaug ;

Kristjansson, Helgi ;

Sulem, Patrick ;

Oddsson, Asmundur ;

Sveinbjornsson, Gardar ;

Steinthorsdottir, Valgerdur ;

Rafnar, Thorunn ;

Masson, Gisli ;

Jonsdottir, Ingileif ;

Olafsson, Isleifur ;

Eyjolfsson, Gudmundur I. ;

Sigurdardottir, Olof ;

Daneshpour, Maryam S. ;

Khalili, Davood ;

Azizi, Fereidoun ;

Swinkels, Dorine W. ;

Kiemeney, Lambertus ;

Quyyumi, Arshed A. ;

Levey, Allan I. ;

Patel, Riyaz S. ;

Hayek, Salim S. ;

Gudmundsdottir, Ingibjorg J. ;

Thorgeirsson, Gudmundur ;

Thorsteinsdottir, Unnur ;

Gudbjartsson, Daniel F. ;

Holm, Hilma ;

Stefansson, Kari .

NATURE GENETICS, 2016, 48 (06) :634-+

[9] S447X variant of the lipoprotein lipase gene, lipids, and risk of coronary heart disease in 3 prospective cohort studies [J].

Jensen, Majken K. ;

Rimm, Eric B. ;

Rader, Daniel ;

Schmidt, Erik B. ;

Sorensen, Thorkild I. A. ;

Vogel, Ulla ;

Overvad, Kim ;

Mukamal, Kenneth J. .

AMERICAN HEART JOURNAL, 2009, 157 (02) :384-390

[10] Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction [J].

Jorgensen, Anders Berg ;

Frikke-Schmidt, Ruth ;

West, Anders Sode ;

Grande, Peer ;

Nordestgaard, Borge G. ;

Tybjaerg-Hansen, Anne .

EUROPEAN HEART JOURNAL, 2013, 34 (24) :1826-+

← 1 2 3 4 →