ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

Autor:	Stitziel NO; 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., Khera AV; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Wang X; Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Bierhals AJ; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri., Vourakis AC; Harvard College, Harvard University, Cambridge, Massachusetts., Sperry AE; Harvard College, Harvard University, Cambridge, Massachusetts., Natarajan P; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Klarin D; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Emdin CA; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Zekavat SM; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Nomura A; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Erdmann J; Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany., Schunkert H; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany., Samani NJ; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom., Kraus WE; Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina., Shah SH; Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina., Yu B; Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas., Boerwinkle E; Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas., Rader DJ; Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Gupta N; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Frossard PM; Center for Non-Communicable Diseases, Karachi, Pakistan., Rasheed A; Center for Non-Communicable Diseases, Karachi, Pakistan., Danesh J; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom., Lander ES; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Gabriel S; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts., Saleheen D; Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Musunuru K; Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: kmus@mail.med.upenn.edu., Kathiresan S; Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. Electronic address: skathiresan@partners.org.
Jazyk:	angličtina
Zdroj:	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.
DOI:	10.1016/j.jacc.2017.02.030
Abstrakt:	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. (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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