Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease
Open accessAbstract
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 .).
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Mendelian randomization evidence suggests that elevated triglycerides linked to genetic variants may be a causal factor for atherosclerotic cardiovascular disease and possibly for premature all-cause mortality.
“More recent evidence from mendelian randomization studies has shown that elevated triglycerides associated with genetic variants may be a causal factor for ASCVD and possibly for premature all-cause mortality.”
From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [4]
The Results section reports that ANGPTL3 loss-of-function carriers had lower triglyceride levels and lower odds of coronary artery disease. That supports a genetic link to coronary disease, but the paper does not establish triglycerides themselves as the causal factor: carriers also had lower LDL and HDL cholesterol. The paper does not report premature all-cause mortality (searched: “premature all-cause mortality”). (LLM, conf=0.84)
Experimental — accuracy not yet measuredANGPTL3 loss-of-function mutations result in lower triglycerides, LDL-C, and a −41% decreased risk of coronary heart diseases, despite reduced HDL-C levels.
“Consequently, ANGPTL3 loss-of-function mutations result in lower triglycerides, LDL-C and a − 41% decreased risk of coronary heart diseases, despite reduced HDL-C levels [146, 147].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [146]
The Results section reports lower triglyceride, LDL-C, and HDL-C levels among ANGPTL3 loss-of-function carriers. It also reports 41% lower adjusted odds of coronary artery disease, not a demonstrated 41% reduction in risk; the claim's causal wording overstates this association. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe AGRE subjects with HABL might have familial combined hypolipidemia, which is primarily secondary to loss-of-function mutations in the genes of the angiopoietin-like proteins, including ANGPTL3.
“The AGRE subjects with HABL might have familial combined hypolipidemia, which is primarily secondary to loss-of-function mutations in the genes of the angiopoietin-like proteins, including ANGPTL3 [90–92]”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [90]
The Results (page not provided) report that an ANGPTL3 loss-of-function variant had previously been observed to segregate with combined hypolipidemia in families, and that carriers had lower lipid levels. The paper does not establish that familial combined hypolipidemia is primarily caused by loss-of-function mutations across angiopoietin-like protein genes. The suggestion about the AGRE subjects is the citing authors’ own inference, not a finding of this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSeveral novel therapies that potently reduce triglyceride levels are currently in development.
“Several novel therapies that potently reduce triglyceride levels are currently in development.[6][7][8]”
From Association of Triglyceride-Lowering <i>LPL</i> Variants and LDL-C–Lowering <i>LDLR</i> Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [6]
Loss-of-function variants in ANGPTL3 are associated with reduced plasma levels of triglyceride, LDL-C, and HDL-C.
“Loss-of-function variants in ANGPTL3 have been associated with reduced plasma levels of TG, LDL-C, and HDL-C.32,64,65”
Individuals with ANGPTL3 LOF variants have low levels of TG, LDL-C, and HDL-C.
“individuals with ANGPTL3 LOF variants have low levels of TG, LDL-C, and HDL-C.32,65”
ANGPTL3 is a genetically validated target for HTG to reduce ASCVD risk.
“ANGPTL3 is a genetically validated target for HTG to reduce ASCVD risk.11,77–79”
From Clinical review on triglycerides (2020) · cites this paper as [79]
Elevated triglycerides appear to be a causal factor for atherosclerotic cardiovascular disease and possibly for premature all-cause mortality, more so when associated with genetic variants.
“elevated triglycerides (TGs) appear to be a causal factor for atherosclerotic CVD (ASCVD) and possibly for premature all-cause mortality, more so when they are associated with genetic variants”
From Update on Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Health (2022) · cites this paper as [7]
PUFAs can reduce triglyceride levels by decreasing lipoproteins with high amounts of triglycerides, such as very-low-density lipoproteins, intermediate-density lipoproteins, chylomicrons, and their remnants.
“PUFAs can reduce TG levels by decreasing lipoproteins with high amounts of TGs, such as very-low-density lipoproteins, intermediate-density lipoproteins, chylomicrons, and their remnants [6,7].”
From Update on Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Health (2022) · cites this paper as [7]
Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids, including lower triglycerides and LDL-C, and with lower rates of coronary artery disease.
“Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids.”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [7]
Previous genetic studies have suggested that reductions in LDL-C and ApoB require near-complete suppression of ANGPTL3 activity.
“Although previous genetic studies have suggested that reductions in LDL-C and ApoB require near-complete suppression of ANGPTL3 activity, 7,13 we did not observe a consistent dose-response relationship for these measures.”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [7]
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- Authors
- Dewey, F. E., Gusarova, V., Dunbar, R. L., O’Dushlaine, C., 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., Stahl, N., Murphy, A. J., Hamon, S., Bouzelmat, A., Zhang, R., Shumel, B., Pordy, R., Gipe, D., Herman, G. A., Sheu, W. H. H., Lee, I.-T., Liang, K.-W., Guo, X., Rotter, J. I., Chen, Y.-D. I., Kraus, W. E., Shah, S. H., Damrauer, S., Small, A., Rader, D. J., Wulff, A. B., Nordestgaard, B. G., Tybjærg-Hansen, A., van den Hoek, A. M., Princen, H. M. G., Ledbetter, D. H., Carey, D. J., Overton, J. D., Reid, J. G., Sasiela, W. J., Banerjee, P., Shuldiner, A. R., Borecki, I. B., Teslovich, T. M., Yancopoulos, G. D., Mellis, S. J., Gromada, J., & Baras, A.
- Affiliations
- National Chung Hsing University (TW)
- Regeneron (United States) (US)
- University of Copenhagen (DK)
- Netherlands Organisation for Applied Scientific Research (NL)
- ORCID
- Gusarova, Viktoria
- Dunbar, Richard L.
- O’Dushlaine, Colm
- Schurmann, Claudia
- Bruse, Shannon
- Dansky, Hayes M.
- Leader, Joseph B.
- Murray, Michael F.
- Ritchie, Marylyn D.
- Kirchner, H. Lester
- Lopez, Alex
- Shao, Weiping
- Stahl, Neil
- Murphy, Andrew J.
- Hamon, Sara
- 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.
- 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.
- Mellis, Scott J.
- Gromada, Jesper
- Baras, Aris
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-07-20
- Volume
- 377
- Issue
- 3
- Pages
- 211-221
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5800308
- OpenAlex
- W2617605538
- Cited by
- 885
- References
- 38
- Citations by year
- 2026: 86 · 2025: 83 · 2024: 80 · 2023: 95 · 2022: 104 · 2021: 123 · 2020: 103 · 2019: 88 · 2018: 85 · 2017: 36 · 2015: 1
- FWCI
- 65.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- TNO Repository (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- University of Pennsylvania
- Regeneron Pharmaceuticals
- University of Pennsylvania Health System
- National Science Council (NSC 101-2314-B-075A-006-MY3, 101-2314-B-075A-006-MY3, MOST 104-2314-B-075A-007, MOST 105)
- Gentofte Hospital
- Ministry of Science and Technology, Taiwan (MOST105-2314-B075A-003)
- National Health Research Institutes (NSC 101-, PH-100-PP-03)
- National Chung-Hsing University
- Rigshospitalet
- National Yang-Ming University
- China Medical University
- Chung Shan Medical University
- Faculty of Health and Medical Sciences, University of Western Australia
- Taichung Veterans General Hospital (TCVGH-1040101C, TCVGH-1040102D, TCVGH-1033102B, 1043104B, TCVGH-1020102D)
- National Institutes of Health (UL1TR000124, UL1TR001881)
- School of Medicine, Duke University
- Perelman School of Medicine, University of Pennsylvania
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
- National Heart, Lung, and Blood Institute (R01HL127009)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ANGPTL3, loss-of-function mutations, evinacumab, monoclonal antibodies, atherosclerotic cardiovascular disease, coronary artery disease, triglycerides, LDL cholesterol, HDL cholesterol, dyslipidemia, atherosclerotic lesion area, genetic association, serum lipids
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Aged, Animals, Antibodies, Monoclonal, Cardiovascular Diseases, Coronary Artery Disease, Disease Models, Animal, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Lipids, Male, Mice, Inbred Strains, Middle Aged, Mutation, Angiopoietins, Dyslipidemias, Atherosclerosis, Lipid Metabolism, Mice
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