CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease

Brian L. Hoh, Departments of 1 Neurosurgery and.
Yan Gong, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida; and
Caitrin W. McDonough, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida; and
Michael F. Waters, Neurology, and.
Adrienne J. Royster, Departments of 1 Neurosurgery and.
Tiffany O. Sheehan, Neurology, and.
Ben Burkley, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida; and
Taimour Y. Langaee, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida; and
J Mocco, Departments of 4 Neurosurgery.
Scott L. Zuckerman, Departments of 4 Neurosurgery.
Nishit Mummareddy, Departments of 4 Neurosurgery.
Marcus L. Stephens, Departments of 4 Neurosurgery.
Christie Ingram, Medicine, and.
Christian M. Shaffer, Medicine, and.
Joshua C. Denny, Medicine, and.
Murray H. Brilliant, Center for Human Genetics Research and.
Terrie E. Kitchner, Center for Human Genetics Research and.
James G. Linneman, Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin.
Dan M. Roden, Medicine, and.
Julie A. Johnson, Division of Cardiovascular Medicine, College of Medicine, and.

Document Type

Article

Abstract

OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, (*)3, (*)8, (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03-0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08-0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06-1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05-1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.

Keywords

CES1 = carboxylesterase 1, CYP = cytochrome P450, ICAD = intracranial atherosclerotic disease, LOF = loss of function, MI = myocardial infarction, PTAS = percutaneous transluminal angioplasty and stenting, SAMMPRIS = Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis, SNP = single-nucleotide polymorphism, TIA = transient ischemic attack, WASID = Warfarin-Aspirin Symptomatic Intracranial Disease, antiplatelet, intracranial atherosclerotic disease, intracranial stenosis, pharmacogenomics, stroke, transient ischemic attack, vascular disorders

Medical Subject Headings

Aged; Aspirin (therapeutic use); Carboxylic Ester Hydrolases (genetics); Clopidogrel; Cytochrome P-450 CYP2C19 (genetics); Female; Gene Frequency; Genotyping Techniques; Heterozygote; Humans; Intracranial Arteriosclerosis (drug therapy, epidemiology, genetics); Ischemic Attack, Transient (drug therapy, epidemiology, genetics); Kaplan-Meier Estimate; Male; Myocardial Infarction (drug therapy, epidemiology, genetics); Platelet Aggregation Inhibitors (therapeutic use); Polymorphism, Single Nucleotide; Prospective Studies; Stroke (drug therapy, epidemiology, genetics); Ticlopidine (analogs & derivatives, therapeutic use)

Publication Date

6-1-2016

Publication Title

Journal of neurosurgery

E-ISSN

1933-0693

Volume

124

Issue

6

First Page

1746

Last Page

51

PubMed ID

26587656

Digital Object Identifier (DOI)

10.3171/2015.6.JNS15795

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