Association between CYP2C9 polymorphisms and ischemic stroke following endovascular neurointervention

Subhashaan Sreedharan; Leonid Churilov; Jianxiong Chan; Marian Todaro; Alan Coulthard; Jeffrey Hocking; Kate Mahady; Peter Mitchell; Richard Dowling; Steven Bush; Patrick Kwan; Bernard Yan

doi:10.1016/j.jstrokecerebrovasdis.2020.104901

Association between CYP2C9 polymorphisms and ischemic stroke following endovascular neurointervention

J Stroke Cerebrovasc Dis. 2020 Aug;29(8):104901. doi: 10.1016/j.jstrokecerebrovasdis.2020.104901. Epub 2020 May 19.

Authors

Affiliations

¹ Melbourne Brain Centre, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3050, Australia.
² Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC 3084, Australia.
³ Department of Medicine, University of Melbourne, Parkville, VIC 3050, Australia; Department of Neuroscience, CCS, Monash University, Melbourne, VIC 3004, Australia.
⁴ Department of Medicine, University of Melbourne, Parkville, VIC 3050, Australia; Department of Neurology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Neuroscience, CCS, Monash University, Melbourne, VIC 3004, Australia.
⁵ Department of Medical Imaging, Royal Brisbane and Women's Hospital, QLD 4029, Australia; Academic Discipline of Medical Imaging, University of Queensland, QLD 4072, Australia.
⁶ Department of Radiology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Radiology, University of Melbourne, Parkville, VIC 3050, Australia.
⁷ Melbourne Brain Centre, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3050, Australia; Department of Neurology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Neuroscience, CCS, Monash University, Melbourne, VIC 3004, Australia; Department of Neurology, Alfred Health, Melbourne, VIC 3004, Australia.
⁸ Melbourne Brain Centre, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Medicine, University of Melbourne, Parkville, VIC 3050, Australia; Department of Neurology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Radiology, Royal Melbourne Hospital, Parkville, VIC 3050, Australia. Electronic address: Bernard.Yan@mh.org.au.

PMID: 32439350
DOI: 10.1016/j.jstrokecerebrovasdis.2020.104901

Abstract

Objective: Polymorphisms in the CYP2C9 gene may be associated with adverse vascular events following endovascular procedures independent of antiplatelet therapy. We aimed to investigate the impact of CYP2C9 loss-of-function polymorphisms on adverse vascular events following neurointervention.

Patients and methods: Consecutive patients undergoing neurointervention were prospectively recruited between 2010 and 2016. Patients were genotyped for the CYP2C9*2 and *3 loss-of-function polymorphisms. On the basis of possible genetic influence on antiplatelet response, ex vivo clopidogrel response was measured using the VerifyNow® P2Y₁₂ Assay. The primary endpoint was the 90-day incidence of adverse vascular events including ischemic stroke.

Results: A total of 229 patients were included. The median age was 57 years (IQR: 49-64), and 158 (69.00%) were female. Eighty-one (35.37%) patients carried at least one CYP2C9 loss-of-function (LOF) allele. After adjustment for stroke risk factors, the 90-day incidence of ischemic stroke was significantly lower in the LOF group compared to the wild type group (1.23% vs 10.14%; OR_adj = 0.16, 95% CI: 0.03-0.91; p = 0.04).

Conclusions: Our results suggest protection against ischemic stroke in carriers of CYP2C9*2 or *3 polymorphisms undergoing neurointervention. Our findings warrant further studies to investigate the mechanisms by which CYP2C9 may influence the risk of ischemic stroke.

Keywords: Antiplatelet; CYP2C9; Clopidogrel; Endovascular; Ischemia; Neurointervention; Stroke.

Publication types

Multicenter Study

MeSH terms

Aged
Brain Ischemia / diagnosis
Brain Ischemia / genetics*
Brain Ischemia / prevention & control*
Cerebrovascular Disorders / therapy*
Clopidogrel / pharmacokinetics
Cytochrome P-450 CYP2C9 / genetics*
Cytochrome P-450 CYP2C9 / metabolism
Endovascular Procedures / adverse effects*
Female
Humans
Male
Middle Aged
Pharmacogenomic Variants*
Pilot Projects
Platelet Aggregation Inhibitors / pharmacokinetics
Polymorphism, Single Nucleotide*
Prospective Studies
Protective Factors
Queensland
Risk Assessment
Risk Factors
Stroke / diagnosis
Stroke / genetics*
Stroke / prevention & control*
Time Factors
Treatment Outcome
Victoria

Substances

Platelet Aggregation Inhibitors
Clopidogrel
CYP2C9 protein, human
Cytochrome P-450 CYP2C9