Genetic variants in CETP increase risk of intracerebral hemorrhage

Christopher D. Anderson, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Guido J. Falcone, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Chia-Ling Phuah, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.Follow
Farid Radmanesh, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
H Bart Brouwers, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Thomas W. Battey, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Alessandro Biffi, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Gina M. Peloso, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Dajiang J. Liu, Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA.
Alison M. Ayres, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
Joshua N. Goldstein, Department of Emergency Medicine, MGH, Boston, MA.
Anand Viswanathan, J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
Steven M. Greenberg, J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
Magdy Selim, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
James F. Meschia, Department of Neurology, Mayo Clinic, Jacksonville, FL.
Devin L. Brown, Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI.
Bradford B. Worrall, Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA.
Scott L. Silliman, Department of Neurology, University of Florida College of Medicine, Jacksonville, FL.
David L. Tirschwell, Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA.
Matthew L. Flaherty, Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH.
Peter Kraft, Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
Jeremiasz M. Jagiella, Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.
Helena Schmidt, Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
Björn M. Hansen, Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Jordi Jimenez-Conde, Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
Eva Giralt-Steinhauer, Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
Roberto Elosua, Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
Elisa Cuadrado-Godia, Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
Carolina Soriano, Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
Koen M. van Nieuwenhuizen, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Catharina J. Klijn, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

Document Type

Article

Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 ) with no heterogeneity across studies (I  = 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 ). INTERPRETATION: 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.

Medical Subject Headings

Adult; Aged; Cerebral Hemorrhage (genetics); Cholesterol Ester Transfer Proteins (genetics); Cholesterol, HDL (blood, genetics); Female; Genetic Predisposition to Disease (genetics); Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Publication Date

11-1-2016

Publication Title

Annals of neurology

E-ISSN

1531-8249

Volume

80

Issue

5

First Page

730

Last Page

740

PubMed ID

27717122

Digital Object Identifier (DOI)

10.1002/ana.24780

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