Association between CYP2C9 polymorphisms and ischemic stroke following endovascular neurointervention

https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104901Get rights and content

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%; ORadj = 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.

Introduction

Endovascular neurointervention is an increasingly preferred method for treating cerebrovascular diseases, such as coiling for intracranial aneurysms.1 Despite dual antiplatelet therapy with clopidogrel and aspirin, thromboembolism is the most frequently reported complication of neurointervention, placing patients at risk of ischemic stroke.1,2 This was traditionally believed to be largely a consequence of the significant inter-individual variability in clopidogrel response. Some patients are hypo-responders to clopidogrel and therefore have an increased risk of thromboembolism.3, 4, 5 This inter-individual variability in clopidogrel response is understood to be due to polymorphisms in the CYP2C family of genes involved in the drug's bioactivation.6

However, there is also growing evidence that genetic polymorphisms in the CYP2C family of genes may be involved with adverse vascular events via mechanisms unrelated to the degree of clopidogrel response. Our group has previously shown that CYP2C19 polymorphisms are associated with an increased risk of ischemic events, independent of the clopidogrel response in those patients.7 Furthermore, it has been estimated that polymorphisms in the CYP2C19 gene only account for 5–12% of the variability in clopidogrel response.8,9 These findings highlight the need to investigate other genetic polymorphisms in the CYP2C family that may be associated with clopidogrel variability and adverse vascular events. It also highlights the need to consider the potential mechanisms by which the CYP2C genes may be associated with adverse vascular events independent of clopidogrel response.

As such, the present study investigates a different gene in the CYP2C family, CYP2C9. Changes in the amino acid sequence of the CYP2C9 gene can decrease the activity of the CYP2C9 enzyme, diminishing its effectiveness in activating clopidogrel, and thereby increasing the risk of ischemic events.10 However, the true association between the CYP2C9 gene and ischemic events is infrequently described in the literature and remains controversial. Brandt et al.11 reported that the CYP2C9*2 and *3 loss-of-function (LOF) alleles were associated with clopidogrel hypo-response. Similarly, Harmsze et al. reported that carriage of the CYP2C9*3 LOF allele was significantly associated with clopidogrel hypo-response as well as postoperative stent thrombosis in a cohort of patients undergoing coronary stenting.12,13 Contrary to this, Funk et al.14 reported that carriage of CYP2C9 LOF alleles could be protective of myocardial infarction.

While the CYP2C9 gene has been studied in several cardiovascular cohorts, there are no studies to our knowledge investigating the effect of CYP2C9 polymorphisms on clopidogrel response and adverse vascular events in neurointerventional cohorts. A better understanding of the effects of these polymorphisms may enable the prevention of adverse clinical outcomes in neurointervention. As such, we aimed to investigate whether the CYP2C9*2 and *3 polymorphisms are associated with clopidogrel response and the incidence of adverse vascular events in patients undergoing endovascular neurointervention.

Section snippets

Study design and population

This was a prospective cohort study. The detailed methodology has been described previously.7 Briefly, eligible patients undergoing elective endovascular neurointervention were consecutively recruited upon admission to the Royal Melbourne Hospital and Royal Brisbane's and Women's Hospital between May 2010 and July 2016. Patients who met the following inclusion criteria were eligible for recruitment: (1) admitted for elective endovascular neurointervention, (2) administered clopidogrel,

Baseline characteristics of study population

A total of 229 patients undergoing elective neurointervention between May 2010 and July 2016 were included in this study. The median age at recruitment was 57 years [IQR: 49–64], and 158 (69.00%) patients were female. The majority of patients (92.14%) were of Caucasian descent. Most (209/229, 91.27%) of the patients were treated for unruptured intracranial aneurysms. A further 18 (7.86%) patients were treated for stenosis of an intracranial artery, and two (0.87%) patients underwent venous

Discussion

Neurointervention is a modern subspecialty and remains restricted to few centers globally. As a result, the body of evidence relating to clinical outcomes in neurointervention is substantially less extensive compared to that of percutaneous coronary intervention. Preliminary studies have demonstrated conflicting findings regarding the associations between CYP2C9 polymorphisms and clopidogrel response as well as ischemic complications in cardiovascular cohorts. To our knowledge, our pilot study

Conclusions

In a study of 229 clopidogrel-treated patients undergoing elective endovascular neurointervention, we found that carriage of either of the CYP2C9*2 or *3 loss-of-function polymorphisms was associated with decreased risk of ischemic stroke, independent of clopidogrel response.

Acknowledgments

None.

Disclosure statement

The authors declare that they have no conflicts of interest in relation to the current work.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

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