Format

Send to

Choose Destination
Ann Neurol. 2016 Nov;80(5):730-740. doi: 10.1002/ana.24780. Epub 2016 Oct 19.

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Author information

1
Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.
2
J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA.
3
Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA.
4
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
5
Departments of Epidemiology and Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.
6
Division of Behavioral Neurology, Department of Neurology, MGH, Boston, MA.
7
Division of Psychiatry, Department of Psychiatry, MGH, Boston, MA.
8
Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA.
9
Department of Emergency Medicine, MGH, Boston, MA.
10
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
11
Department of Neurology, Mayo Clinic, Jacksonville, FL.
12
Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI.
13
Departments of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA.
14
Department of Neurology, University of Florida College of Medicine, Jacksonville, FL.
15
Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA.
16
Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH.
17
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.
18
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
19
Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
20
Division of Neurology, Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
21
Neurovascular Research Unit, Department of Neurology, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
22
Program in Inflammation and Cardiovascular Disorders, Municipal Institute of Medical Investigation-Hospital of the Sea, Autonomous University of Barcelona, Barcelona, Spain.
23
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
24
Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
25
Division of Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
26
Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
27
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
28
Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Brescia, Italy.
29
Department of Neurology, Medical University of Graz, Graz, Austria.
30
Division of Neuroradiology, Department of Radiology, Medical University of Graz, Graz, Austria.
31
Neurovascular Research Laboratory and Neurovascular Unit, Research Institute, Vall d'Hebron Hospital, Autonomous University of Barcelona, Barcelona, Spain.
32
Stroke Pharmacogenomics and Genetics, Terrassa Mutual Teaching and Research Foundation, Terrassa Mutual Hospital, Terrassa, Spain.
33
Department of Neurology, University of Arizona, Tucson, AZ.
34
Department of Neurology, Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore, MD.
35
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
36
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC.
37
Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI.
38
Division of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
39
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI.
40
Cardiovascular Disease Prevention Center, MGH, Boston, MA.

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 × 10-4 ) 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 ).

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.

PMID:
27717122
PMCID:
PMC5115931
DOI:
10.1002/ana.24780
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center