The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.
Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Open accessAbstract
BACKGROUND: High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown. METHODS: Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants. RESULTS: Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04). CONCLUSIONS: Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent data from genetic studies utilizing a Mendelian randomization design have consistently linked both non-fasting TG levels as well as remnant cholesterol to increased risk of CVD events and all-cause mortality.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [107]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“loss-of-function variants in APOC3 confer protection against coronary artery disease, independent of LDL cholesterol levels [60, 112]”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [112]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“rare loss-of-function mutations in the lipoprotein lipase (LPL) gene are associated with higher plasma triglyceride levels and a higher risk of cardiovascular disease”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“while rare, loss-of-function mutations in the APOC3, ANGPTL3, and ANGPTL4 genes, which encode for natural inhibitors of LPL, are associated with lower triglyceride levels and a corresponding lower risk of cardiovascular disease.[9][10][11][12][13]”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [10]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In contrary, loss-of-function mutations of the ApoC-III are associated with a lower risk of CVD [170–172].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [171]
The cited source says what the claim attributes to it.
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”
The cited source says what the claim attributes to it.
In the citing paper
“and is a genetically validated target to reduce ASCVD risk.8–10,64–66”
From Clinical review on triglycerides (2020) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“Apolipoprotein C-III is a central regulator of triglyceride metabolism that limits the clearance of triglyceride-rich lipoproteins through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoprotein remnants. 6-8”
From Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“defects in genes controlling TG metabolism, including APOC3, ANGPTL3 and ANGPTL4 that have been linked to reduced TG and are associated with reduced coronary calcification25 or reduced CVD risk.26-30”
From Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?: New Insights From the Framingham Offspring Study (2016) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Low-density lipoprotein (LDL) cholesterol and triglyceride-rich remnant lipoproteins are causally associated with risk of atherosclerotic vascular disease [3][4][5][6]”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [4]
In the citing paper
“ApoCIII is a predictor of CV disease and reduced apoCIII levels may have direct beneficial effects on the vessel wall, such as by reducing its retention of LDL particles (LDL-apoCIII) [48–50].”
In the citing paper
“ApoCIII is a predictor of CV disease and reduced apoCIII levels may have direct beneficial effects on the vessel wall, such as by reducing its retention of LDL particles (LDL-apoCIII) [48–50].”
In the citing paper
“Some rare heterozygous loss-of-function (LOF) variants are associated with reduced TG levels. These patients show protection from ASCVD providing important evidence for a causal role of TG for ASCVD.”
From Clinical review on triglycerides (2020) · cites this paper as [10]
In the citing paper
“Such LOF variants of APOC3 are also associated with reduced ASCVD risk.10”
From Clinical review on triglycerides (2020) · cites this paper as [10]
In the citing paper
“Furthermore, loss of function mutations are associated with low TGs as well as with reduced risk for CVD. 106,107”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [107]
In the citing paper
“Furthermore, loss of function mutations are associated with low TGs as well as with reduced risk for CVD.106,107”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [107]
In the citing paper
“Recent data from genetic studies utilizing a Mendelian randomization design have consistently linked both non-fasting TG levels as well as remnant cholesterol to increased risk of CVD events and all-cause mortality.86,107”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [107]
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Citations
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Metadata
- Authors
- Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G., & Tybjærg-Hansen, A.
- Affiliations
- University of Copenhagen (DK)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-07-03
- Volume
- 371
- Issue
- 1
- Pages
- 32-41
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2052644460
- Semantic Scholar
- 55f5e169d6f4d9a568cca4bbafe0790022e8bc16
- Cited by
- 919
- References
- 39
- Citations by year
- 2026: 50 · 2025: 76 · 2024: 49 · 2023: 46 · 2022: 65 · 2021: 64 · 2020: 95 · 2019: 71 · 2018: 71 · 2017: 99 · 2016: 113 · 2015: 87 · 2014: 32
- FWCI
- 75.40
- 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) (submittedVersion)
- Funders
- Gentofte Hospital
- Rigshospitalet
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- apolipoprotein C-III, ischemic vascular disease, ischemic heart disease, cardiovascular risk, heterozygosity, genetic variants, triglyceride lowering, general population, hypertriglyceridemia, genetic epidemiology, Mendelian randomization
- MeSH terms
- Adult, Aged, Female, Genotype, Humans, Ischemia, Cholesterol, LDL, Liver, Male, Middle Aged, Mutation, Risk Factors, Triglycerides, Incidence, Myocardial Ischemia, Sequence Analysis, DNA, Apolipoprotein C-III, Exome
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