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ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2017 Apr 25; Vol. 69 (16), pp. 2054-2063. Date of Electronic Publication: 2017 Apr 03. - Publication Year :
- 2017
-
Abstract
- 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.<br />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.<br />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.<br />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).<br />Conclusions: ANGPTL3 deficiency is associated with protection from CAD.<br /> (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Angiopoietin-Like Protein 3
Angiopoietin-like Proteins
Angiopoietins blood
Angiopoietins genetics
Animals
Atherosclerosis genetics
Case-Control Studies
Female
Humans
Lipids blood
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Mutation, Missense
Myocardial Infarction blood
Risk Factors
Angiopoietins deficiency
Coronary Artery Disease genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 69
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 28385496
- Full Text :
- https://doi.org/10.1016/j.jacc.2017.02.030