Pharmacogenetics of CYP2C19 genetic polymorphism on clopidogrel response in patients with ischemic stroke from Saudi Arabia

Abstract

Objective:To elucidate the degree of genetic polymorphisms CYP2C19 (CYP2C19*2, CYP2C19*3) of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel response in patients with acute ischemic stroke from Saudi Arabia.Methods:A case-control study carried out at Neurology Clinics at Asser Central Hospital, Abha, Kingdom of Saudi Arabia from October 2015 to January 2016 and included 25 stroke patients responding to clopidogrel therapy and 25 stroke patients non responding to clopidogrel monotherapy. After obtaining their informed consent, the blood samples were collected and genotyped for CYP2C19 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP Method). Allele frequencies were derived from genotypic data and platelet aggregation was measured using multiple electrode aggregometry on the multiplate analyser. Chi Square tests, p-values, odds ratio (OR) and corresponding confidence intervals were calculated for each polymorphism.Results:The CYP2C19*2 (681G>A) and CYP2C19*3 (636 G>A) polymorphism were seen to be in Hardy–Weinberg equilibrium and showed significant allelic and genotypic association between responders and non-responders to clopidogrel (p<0.01). The CYP2C19*2: allelic chi-square=21.49, p=0.000036, OR=5.52 (2.42-12.83); Genotypic Chi-square=10.27, p=0.001, OR=7.88 (1.78-9.73). The CYP2C19*3: Allelic chi-square=11.66, p=0.0006, OR=3.45 (1.57-7.70); genotypic chi-square=4.37, p=0.036, OR=3.69 (0.90-5.81). The variant allele (homozygous and homozygous Mutant) showed significant influence on platelet inhibition and the antiplatelet effect of clopidogrel in ischemic stroke.Conclusion:Our findings provide certain evidence on the genetic effect of CYP2C19 on clopidogrel responsiveness in stroke patients from Saudi Arabia.

Anti-Platelet Therapy in Mild Cerebral Infarction Patients on the Basis of CYP2C19 Metabolizer Status

“…Thus, it is recommended that monotherapy with clopidogrel is appropriate if patients are intolerant to aspirin because of allergy or gastrointestinal side effects or to dipyridamole because of headache. However, the clinical response to clopidogrel varies widely in patients with cardiovascular and/or cerebrovascular diseases and it is closely related to the CYP2C19 gene polymorphism 11 –13 . For example, some studies show CYP2C19*2 carriers have lower levels of active clopidogrel metabolites, higher on-treatment platelet aggregation, and higher risk for major adverse cardiovascular events as compared to noncarriers 15 .…”

“…Several studies have investigated the influence of CYP2C19 genotypes and metabolizer status on the efficacy of clopidogrel 11 –13 . Although these studies consistently suggest CYP2C19 genotypes are closely related to the clopidogrel response, the influence of CYP2C19 metabolizer status on the clopidogrel response is still inconclusive.…”

Molecular genetic studies in Saudi population; identified variants from GWAS and meta-analysis in stroke

“…In our study, the rs11053646 polymorphism in OLR1 gene was associated, and our results confirm the earlier meta-analysis studies, concluding as may contribute to the risk of disease susceptibility (Au et al, 2015). In Saudi Arabia, there are limited studies have been documented with stroke, and among them, Alhazzani et al (2017) performed the molecular study with CYPC219 genetic polymorphisms and found to be associated. Al-Shenqiti et al (2017) performed the detailed study of stroke who were effected for the first time.…”

The Effect of CYP2C19 and Nongenetic Factors on Clopidogrel Responsiveness in the MENA Region: A Systematic Review

“…Hardy-Weinberg equilibrium was tested and reported in only 9 studies. 28,[30][31][32][36][37][38][39][40]…”

“…The definition of clopidogrel responsiveness varied across the included studies. Among the 9 studies, the cutoff value for HTPR was expressed using platelet aggregation in 2 studies 26,40 whereas it was expressed as percentage of relative platelet inhibition in 1 study. 31 Two of the studies expressed the cutoff value for HTPR by the PRU.…”