The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index.
ANGPTL3 Deficiency and Protection Against Coronary Artery Disease
Open accessAbstract
BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.
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In the citing paper
“Similarly, with genetic studies supporting the role of several novel therapeutic targets (eg, apo C-III and ANGPTL3) in atherosclerosis, ongoing clinical trials using RNA interference therapy (antisense oligonucleotides and small interfering RNAs) have the potential to further inform our understanding of the triglyceride-based atherosclerotic pathways (120,121).”
From 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia (2021) · cites this paper as [121]
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In the citing paper
“Carriers of loss-of-function (LOF) variants in ANGTPL3 present with low triglyceride, low LDL (low-density lipoprotein) cholesterol (LDL-C), and low HDL (high-density lipoprotein) cholesterol (HDL-C) plasma levels,1 as well as a decreased risk for cardiovascular disease compared with non-carriers.2,3”
In the citing paper
“Mendelian randomization studies focused on variants in the genes encoding apoAV, apoCIII, lipoprotein lipase (LpL) and the angiopoietin-like proteins 3, 4, and 8 (ANGPTL3, ANGPTL4, and ANGPTL8) have been highly informative.29–35”
In the citing paper
“Loss-of-function variants in ANGPTL3 have been associated with reduced plasma levels of TG, LDL-C, and HDL-C.32,64,65”
In the citing paper
“individuals with ANGPTL3 LOF variants have low levels of TG, LDL-C, and HDL-C.32,65”
In the citing paper
“These hypotriglyceridaemic states contrast with mild HTG and increased ASCVD risk seen with heterozygous LOF mutations in APOA5.11”
From Clinical review on triglycerides (2020) · cites this paper as [11]
In the citing paper
“Similarly, heterozygous LOF variants in ANGPTL311 and ANGPTL412 genes are associated with reductions both in plasma TG and ASCVD risk.”
From Clinical review on triglycerides (2020) · cites this paper as [11]
In the citing paper
“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 [11]
In the citing paper
“Recently, the EpanoVa fOr Lowering Very high triglyceridEs II (EVOLVE II) trial confirmed the efficacy of omega-3 fatty acids in lowering serum TGs [327].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [327]
In the citing paper
“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 [12]
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Citations
Cites
Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728
Self-citationSequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181
Self-citationGenomewide Association Analysis of Coronary Artery Disease
Samani, N. J., Erdmann, J., Hall, A. S., Hengstenberg, C., Mangino, M., Mayer, B., Dixon, R. J., Meitinger, T., Braund, P., Wichmann, H.-E., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072366 · Cited by 2,044
Self-citationGenetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
Clarke, R., Peden, J. F., Hopewell, J. C., Kyriakou, T., Goel, A., Heath, S. C., Parish, S., Barlera, S., Franzosi, M. G., Rust, S., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0902604 · Cited by 1,671
A Common Allele on Chromosome 9 Associated with Coronary Heart Disease
McPherson, R., Pertsemlidis, A., Kavaslar, N., Stewart, A., Roberts, R., Cox, D. R., Hinds, D. A., Pennacchio, L. A., Tybjaerg-Hansen, A., Folsom, A. R., et al. (2007) · Science · doi:10.1126/science.1142447 · Cited by 1,587
Self-citationLoss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071
Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G., & Tybjærg-Hansen, A. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1308027 · Cited by 919
Exome Sequencing, ANGPTL3 Mutations, and Familial Combined Hypolipidemia
Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1002926 · Cited by 754
Self-citationTobin, M. D., Sheehan, N. A., Scurrah, K. J., & Burton, P. R. (2005) · Statistics in Medicine · doi:10.1002/sim.2165 · Cited by 695
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1 of the 45 references couldn’t be matched to a known paper.
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Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854
Ginsberg, H. N., Packard, C. J., Chapman, M. J., Borén, J., Aguilar-Salinas, C. A., Averna, M., Ference, B. A., Gaudet, D., Hegele, R. A., Kersten, S., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab551 · Cited by 979
Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease
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., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1612790 · Cited by 885
Self-citationSandesara, P. B., Virani, S. S., Fazio, S., & Shapiro, M. D. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00184 · Cited by 608
Metadata
- Authors
- Stitziel, N. O., Khera, A. V., Wang, X., Bierhals, A. J., Vourakis, A. C., Sperry, A. E., Natarajan, P., Klarin, D., Emdin, C. A., Zekavat, S. M., Nomura, A., Erdmann, J., Schunkert, H., Samani, N. J., Kraus, W. E., Shah, S. H., Yu, B., Boerwinkle, E., Rader, D. J., Gupta, N., Frossard, P. M., Rasheed, A., Danesh, J., Lander, E. S., Gabriel, S., Saleheen, D., Musunuru, K., & Kathiresan, S.
- Affiliations
- Washington University in St. Louis (US)
- Broad Institute (US)
- Harvard University (US)
- Institute for Integrative and Experimental Genomics (DE)
- German Centre for Cardiovascular Research (DE)
- University of Leicester (GB)
- Duke University (US)
- Baylor College of Medicine (US)
- University of Pennsylvania (US)
- Center for Non-Communicable Diseases (PK)
- University of Cambridge (GB)
- Corresponding author
- Stitziel, Nathan O.
- ORCID
- Stitziel, Nathan O.
- Khera, Amit V.
- Bierhals, Andrew J.
- Sperry, Alexandra E.
- Natarajan, Pradeep
- Klarin, Derek
- Emdin, Connor A.
- Zekavat, Seyedeh M.
- Nomura, Akihiro
- Erdmann, Jeanette
- Schunkert, Heribert
- Samani, Nilesh J.
- Kraus, William E.
- Shah, Svati H.
- Yu, Bing
- Boerwinkle, Eric
- Rader, Daniel J.
- Gupta, Namrata
- Danesh, John
- Lander, Eric S.
- Gabriel, Stacey
- Saleheen, Danish
- Musunuru, Kiran
- Kathiresan, Sekar
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 69
- Issue
- 16
- Pages
- 2054-2063
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC5404817
- OpenAlex
- W2604768034
- Cited by
- 467
- References
- 45
- Citations by year
- 2026: 38 · 2025: 39 · 2024: 46 · 2023: 58 · 2022: 57 · 2021: 70 · 2020: 44 · 2019: 36 · 2018: 54 · 2017: 23
- FWCI
- 33.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Harvard Catalyst
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (RG/08/014/24067)
- National Institutes of Health (5t32hl007734-30, KL2TR001100)
- Medical Research Council (MR/L003120/1)
- National Heart, Lung, and Blood Institute (R01HL127564, K08HL114642, R33HL120781, R21HL120781, T-32HL007734, RC2HL101834, R01HL118744, R01HL131961)
- National Human Genome Research Institute (UM1HG008895, U54HG003067, UM1HG008853)
- Fogarty International Center (RC1TW008485)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- ANGPTL3, coronary artery disease, loss-of-function mutations, myocardial infarction, triglycerides, LDL cholesterol, genetic risk, heterozygous carriers, hypolipidemic effect, first-degree relatives, loss-of-function screening
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Adult, Animals, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Middle Aged, Myocardial Infarction, Risk Factors, Case-Control Studies, Mice, Knockout, Mutation, Missense, Angiopoietins, Atherosclerosis
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