ArticleEuropean heart journal open2024
Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk.
Article in European heart journal open, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Review
- Strenuous Exercise and Quercetin Supplementation Differentially Alter Lipid Metabolism in C57BL/6J Mice.Journal of lipid and atherosclerosis · 2026Article
- Angiopoietin-like protein 3 complete and partial deficiency markedly accelerates apolipoprotein B48 and B100 metabolism in triglyceride-rich lipoproteins in humans.Journal of internal medicine · 2026Article
- Inherited risk of coronary artery disease: redefining care with imaging and genetics.Nature reviews. Cardiology · 2026Review
- Residual cardiovascular risk in coronary artery disease: from pathophysiology to established and novel therapies.Nature reviews. Cardiology · 2026Review
- Shared proteomic landscape between arteriosclerosis and cardiovascular endpoints: a Mendelian randomization and observational study integrating AlphaFold3 for structural prediction.Cardiovascular research · 2026Observational
- Leveraging Mendelian randomization to inform drug discovery and development for ischemic stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.Cardiovascular diabetology · 2026Article
- Apolipoprotein C3 exacerbates vascular calcification by promoting ferroptosis via the TLR2/AMPK pathway in vascular smooth muscle cells.Redox biology · 2026Article
- Gene therapy and genome editing for lipoprotein disorders.European heart journal · 2025Review
- ANGPTL4: A Comprehensive Review of 25 Years of Research.Cancers · 2025Review
- Elevated apolipoprotein C3 heightens atherosclerosis risk by mediating arterial accumulation of free cholesterol and local inflammation in diabetes.Research square · 2025Article
- Review
- A multivariable cis-Mendelian randomization method robust to weak instrument bias and horizontal pleiotropy bias.Briefings in bioinformatics · 2025Article
- Remnant cholesterol concentrations best explain the cardiovascular benefit of APOC3 genetic inhibition: a drug target Mendelian randomization study.European heart journal open · 2025Article
- ANGPTL3 and residual atherosclerotic risk: from lipid metabolism to therapeutic targeting.Frontiers in endocrinology · 2025Review
- Intervention, improved prevention, imaging, inflammation, and innovation: the five I's cardiovascular highlights inEuropean heart journal open · 2025Article
- SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes induced by type 2 diabetes.Cardiovascular diabetology · 2024Article
- Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges.eGastroenterology · 2024Review
- Characterization of sexual dimorphism in ANGPTL4 levels and function.Journal of lipid research · 2024Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aims: APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation. Methods and results: We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47-0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57-0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82-0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58-0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns. Conclusion: Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.
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