title: Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.
abstract: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease.
  
  
  
  To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD).
  
  
  
  In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis.
  
  
  
  Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels.
  
  
  
  Circulating lipid levels and CAD.
  
  
  
  Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides.
  
  
  
  The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston.
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, Massachusetts5Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.affiliation: Regeneron Genetics Center, Tarrytown, New Jersey.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Dushlaine
authors.affiliation: Department of Public Health Sciences, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Dajiang
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri9Department of Genetics, Washington University School of Medicine, St Louis, Missouri10McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Connor A
authors.initials: CA
authors.lastname: Emdin
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Regeneron Genetics Center, Tarrytown, New Jersey.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy12Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Italy12Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Ospedale Niguarda, Milano, Italy.
authors.forename: Piera Angelica
authors.initials: PA
authors.lastname: Merlini
authors.affiliation: Department of Medicine, University of Mississippi Medical Center, Jackson.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Correa
authors.affiliation: Munich Heart Alliance, München, Germany16Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kessler
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bown
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds University, Leeds, United Kingdom.
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.affiliation: NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murray
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: H Lester
authors.initials: HL
authors.lastname: Kirchner
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Leader
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lavage
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: J Neil
authors.initials: JN
authors.lastname: Manus
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Dustin N
authors.initials: DN
authors.lastname: Hartzel
authors.affiliation: NIHR Leicester Cardiovascular Biomedical Research Unit, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.affiliation: Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom24Wellcome 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, University of Oxford, Oxford, United Kingdom24Wellcome 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 S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom27Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom28NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom29Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.affiliation: Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy31Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ardissino
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor33Department of Human Genetics, University of Michigan, Ann Arbor34Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Cristen
authors.initials: C
authors.lastname: Willer
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: Regeneron Genetics Center, Tarrytown, New Jersey.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts2Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston3Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D014280:Triglycerides / Q000097:blood
chemical_list: D008074:Lipoproteins; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase