title: Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.
abstract: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.
  
  
  
  This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.
  
  
  
  Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.
  
  
  
  Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
  
  
  
  Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
authors.affiliation: Center for Human Genetic Research, 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: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.affiliation: Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Lawson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington.
authors.forename: Traci M
authors.initials: TM
authors.lastname: Bartz
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Xuan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Center for Human Genetic Research, 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: 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: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, Washington.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany, and Munich Heart Alliance, München, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kessler
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy, and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, Washington.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington.
authors.forename: Bruce
authors.initials: B
authors.lastname: Psaty
authors.affiliation: Departments of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Public Health and Primary Care, University of Cambridge, Cambridge, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge and National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany, and Munich Heart Alliance, München, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Lander
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Correa
authors.affiliation: Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Ospedale Niguarda, Milano, Italy.
authors.forename: Piera Angelica
authors.initials: PA
authors.lastname: Merlini
authors.affiliation: Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, University of Parma, Parma, Italy, and ASTC: Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ardissino
authors.affiliation: Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
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 Human Genetic Research, 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: skathiresan1@mgh.harvard.edu.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D053299:Apolipoprotein B-100 / Q000235:genetics*; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000453:epidemiology*; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: coronary artery disease; gene sequencing; genetics; low-density lipoprotein cholesterol