title: ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
authors.affiliation: 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.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Khera
authors.affiliation: Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bierhals
authors.affiliation: Harvard College, Harvard University, Cambridge, Massachusetts.
authors.forename: A Christina
authors.initials: AC
authors.lastname: Vourakis
authors.affiliation: Harvard College, Harvard University, Cambridge, Massachusetts.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Sperry
authors.affiliation: 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.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: 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.
authors.forename: Derek
authors.initials: D
authors.lastname: Klarin
authors.affiliation: 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.
authors.forename: Connor A
authors.initials: CA
authors.lastname: Emdin
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Seyedeh M
authors.initials: SM
authors.lastname: Zekavat
authors.affiliation: 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.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.affiliation: Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Center for Non-Communicable Diseases, Karachi, Pakistan.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Frossard
authors.affiliation: Center for Non-Communicable Diseases, Karachi, Pakistan.
authors.forename: Asif
authors.initials: A
authors.lastname: Rasheed
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: 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.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: 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.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D000328:Adult; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020125:Mutation, Missense; D009203:Myocardial Infarction / Q000097:blood; D012307:Risk Factors
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D008055:Lipids
keywords: human genetics; loss-of-function mutations; myocardial infarction