title: Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.
abstract: BACKGROUND
  Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.
  
  
  OBJECTIVE
  The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD.
  
  
  METHODS
  We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.
  
  
  RESULTS
  One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.
  
  
  CONCLUSIONS
  Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.
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: Connor A
authors.initials: CA
authors.lastname: Emdin
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: 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: 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: Derek
authors.initials: D
authors.lastname: Klarin
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: Departments of Medicine, Genetics, and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
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: Akihiro
authors.initials: A
authors.lastname: Nomura
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: Seyedeh M
authors.initials: SM
authors.lastname: Zekavat
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Biomedical Sciences, Humanitas University and Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Department of Biomedical Sciences, Humanitas University and Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Ospedale Niguarda, Milan, Italy.
authors.forename: Piera Angelica
authors.initials: PA
authors.lastname: Merlini
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: Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany; Munich Heart Alliance, München, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kessler
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: Departments of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, 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: Departments of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Leicester, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.affiliation: Departments of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, 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 & Genetics, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.affiliation: Cardiovascular Epidemiology & Genetics, IMIM (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 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: Department of Computational Medicine and Bioinformatics, Department of Human Genetics, and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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, Michigan.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.affiliation: National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts; Sections of Cardiology, Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
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 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, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; 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: Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, University of Parma, Parma, Italy; ASTC: Associazione 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: Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
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
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authors.lastname: Kathiresan
mesh_terms: D015415:Biomarkers; D003327:Coronary Disease / Q000097:blood / Q000235:genetics* / Q000628:therapy; D004247:DNA / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood* / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D017270:Lipoprotein(a); D004247:DNA
keywords: coronary heart disease; genetics; phenome-wide association study; single nucleotide polymorphism