Genetic variants in CETP increase risk of intracerebral hemorrhage

Authors

• 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

Recommended Citation

Anderson, Christopher D.; Falcone, Guido J.; Phuah, Chia-Ling; Radmanesh, Farid; Brouwers, H Bart; Battey, Thomas W.; Biffi, Alessandro; Peloso, Gina M.; Liu, Dajiang J.; Ayres, Alison M.; Goldstein, Joshua N.; Viswanathan, Anand; Greenberg, Steven M.; Selim, Magdy; Meschia, James F.; Brown, Devin L.; Worrall, Bradford B.; Silliman, Scott L.; Tirschwell, David L.; Flaherty, Matthew L.; Kraft, Peter; Jagiella, Jeremiasz M.; Schmidt, Helena; Hansen, Björn M.; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; van Nieuwenhuizen, Koen M.; and Klijn, Catharina J., "Genetic variants in CETP increase risk of intracerebral hemorrhage" (2016). Neurology. 1721.
https://scholar.barrowneuro.org/neurology/1721