title: Genetic variants in CETP increase risk of intracerebral hemorrhage.
abstract: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.
  
  
  
  We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.
  
  
  
  Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4) with no heterogeneity across studies (I2= 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6).
  
  
  
  Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Falcone
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Phuah
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Farid
authors.initials: F
authors.lastname: Radmanesh
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: H Bart
authors.initials: HB
authors.lastname: Brouwers
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Thomas W K
authors.initials: TW
authors.lastname: Battey
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Division of Behavioral Neurology, Department of Neurology, MGH, Boston, MA.|Division of Psychiatry, Department of Psychiatry, MGH, Boston, MA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
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authors.initials: GM
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authors.affiliation: Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA.
authors.forename: Dajiang J
authors.initials: DJ
authors.lastname: Liu
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Ayres
authors.affiliation: Department of Emergency Medicine, MGH, Boston, MA.
authors.forename: Joshua N
authors.initials: JN
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authors.affiliation: J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
authors.forename: Anand
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authors.affiliation: J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
authors.forename: Steven M
authors.initials: SM
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authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: Magdy
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authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL.
authors.forename: James F
authors.identifier: 0000-0002-4475-8142
authors.initials: JF
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authors.affiliation: Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI.
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authors.initials: DL
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authors.affiliation: Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA.
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authors.affiliation: Department of Neurology, University of Florida College of Medicine, Jacksonville, FL.
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authors.affiliation: Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA.
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authors.affiliation: Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH.
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authors.affiliation: Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
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authors.affiliation: Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.|Division of Neurology, Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Roberto
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Carolina
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authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
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authors.identifier: 0000-0002-4815-002X
authors.initials: KM
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authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
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authors.affiliation: Division of Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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authors.affiliation: Division of Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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authors.affiliation: Division of Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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authors.affiliation: Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy.
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authors.affiliation: Neurovascular Research Laboratory and Neurovascular Unit, Research Institute, Vall d'Hebron Hospital, Autonomous University of Barcelona, Barcelona, Spain.|Stroke Pharmacogenomics and Genetics, Terrassa Mutual Teaching and Research Foundation, Terrassa Mutual Hospital, Terrassa, Spain.
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authors.affiliation: Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.|Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
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authors.affiliation: Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.|J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.|Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
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mesh_terms: D000328:Adult; D000368:Aged; D002543:Cerebral Hemorrhage / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL