• J. Am. Coll. Cardiol. · Apr 2017

    ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

    • Nathan O Stitziel, Amit V Khera, Xiao Wang, Andrew J Bierhals, A Christina Vourakis, Alexandra E Sperry, Pradeep Natarajan, Derek Klarin, Connor A Emdin, Seyedeh M Zekavat, Akihiro Nomura, Jeanette Erdmann, Heribert Schunkert, Nilesh J Samani, William E Kraus, Svati H Shah, Bing Yu, Eric Boerwinkle, Daniel J Rader, Namrata Gupta, Philippe M Frossard, Asif Rasheed, John Danesh, Eric S Lander, Stacey Gabriel, Danish Saleheen, Kiran Musunuru, Sekar Kathiresan, and PROMIS and Myocardial Infarction Genetics Consortium Investigators.
    • Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Electronic address: nstitziel@wustl.edu.
    • J. Am. Coll. Cardiol. 2017 Apr 25; 69 (16): 2054-2063.

    BackgroundFamilial 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.ObjectivesThe 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.MethodsWe 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.ResultsThe 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).ConclusionsANGPTL3 deficiency is associated with protection from CAD.Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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