Balkan Journal of Medical Genetics

EFFECTS OF CYP2C19 AND P2Y12 GENE POLYMORPHISMS ON CLINICAL RESULTS OF PATIENTS USING CLOPIDOGREL AFTER ACUTE ISCHEMIC CEREBROVASCULAR DISEASE
Sen HM1,*, Silan F2, Silan C3, Degirmenci Y4, Ozisik Kamaran HI1
*Corresponding Author: Halil Murat Sen, M.D., Department of Neurology, School of Medicine, Çanakkale Onsekiz Mart Üniversity, Barboros Mah., Terzioðlu Kampüsü, Týp Fakültesi, Çanakkale, Turkey. Tel : +90-286-218-37-38. Fax : +90-286-218-00-18. E-mail: hmuratsen@gmail.com
page: 37

DISCUSSION

Clopidogrel is used to prevent the development of a new ischemic attack [1]. Clopidogrel prevents ICVD; it has also been shown to be effective in patients with peripheral artery disease who use clopidogrel [14,17]. However, after using the drug, individual differences in response were observed and this situation has brought insufficiency of clopidogrel treatment to the agenda [18,19]. In our study, in spite of using clopidogrel, three of our 51 patients developed ICVD during at least 1 year of follow-up and these patients began taking warfarin instead. When these patients began clopidogrel treatment, they had no history of warfarin use. When the CYP2C19 gene was evaluated in our patients with recurring ICVD, one patient was homozygous for *2/*2, and two were heterozygous for *1/*2. In the patients with recurring ICVD, the *2 allele frequency was significantly higher than in the group without recurring ischemia (p <0.0001). In our three patients, recurring ICVD and subsequent necessity to change medication, was linked to the CYP2C19 gene polymorphism. This is because clopidogrel is a prodrug and transforms into its effective metabolite through the action of CYP2 C19 enzyme in the liver CYP450 enzyme family. The transformation of clopidogrel into active metabolite reduces when linked to CYP2C19 genetic variations [5]. The reasons for clopidogrel resistance are multifactorial and other reasons include medication interactions and insufficient use of the drug [20]. In medication interactions, proton pump inhibitors (PPI) attract attention because PPI, especially, are frequently prescribed with clopidogrel. Proton pump inhibitors use reduces the effects of clopidogrel on platelets. This situation is worrisome as it may cause recurring strokes [21]. In our patient group, there was no use of PPI by the patients who had recurring strokes. Similarly, patients who did not use the medication sufficiently, another cause of unresponsiveness to medication, were not included in the study. Recently, there were increasing worries about the failure in effectiveness of clopidogrel, due to genetic variations in CYP2C19 in the CYP450 enzyme family that facilitates metabolism of the medication [20]. As a result, the American Food and Drug Administration recommended that though not required, testing should be carried out before use, due to possible low effectiveness [22]. In our patient group, none of the patients had any tests before beginning the drug as the current social security system in our country does not cover the cost of the tests. Together with covering the cost of the tests, it is estimated that about 3.0% (2.0-14.0%) of the population do not metabolize clopidogrel well [23]. Those with P2Y12 polymorphism using clopidogrel for peripheral artery disease are reported to have four times more ICVD than those with wild type genotypes. It has been shown that medications like aspirin are not affected by variations in P2Y12. These results may be linked to genetic variations in the target receptors for clopidogrel [14]. However, in our study, no patient was identified with the P2Y12 polymorphism. In our patient group, no single person had both P2Y12 and CYP2C19 gene polymorphisms, so haplotype analysis was not possible. As a result, the clinical effects of such a combination could not be identified in our study. However, in a previous study of stent patients with acute coronary syndrome, the clinical results of clopidogrel treatment were monitored. It was shown that a combination of P2Y12 and CYP2C19 gene polymorphisms produced worse negative clinical results than each polymorphism alone [16]. The increase in the number of polymorphisms increasing the unresponsiveness to the drug was a sign that genetic variations are very important for clopidogrel effectiveness. The CYP2C19 and P2Y12 gene polymorphisms may cause recurring stroke attacks linked to an insufficient response to ICVD treatment. Stroke is among the top causes of mortality and morbidity. Repeated ischemic stroke events increase this risk further. As a result, genetic testing before medication use is important for human life, standard of living and economic burden. Declaration of Interest. The present study was supported by the Department of Scientific Research Projects Commission, Çanakkale Onsekiz Mart University, Çanakkale, Turkey. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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