The CYP2C19 genotypes and its effect on clopidogrel as an anti-platelet drug among the Arab population.

Sir,

Patients with cardiovascular diseases (CVDs) include stroke, coronary artery disease, deep-vein thrombosis, and pulmonary embolism are at high risk of recurrent cardiovascular events (CVEs), because of that, it is necessary to prevent further coagulations for those patients.[1] Many antiplatelet and anticoagulant drugs had been studied about their safety and efficacy on patients with CVDs to prevent recurrent CVEs in future.[2]

Clopidogrel is a common anti-platelet drug used as prophylaxis to protect patients with previous coronary artery thrombosis from recurrent CVEs.[3] Clopidogrel depends on various cytochrome P450 enzymes (CYP450) to be converted to its active metabolite. These enzymes include CYP3A4, CYP1A2, CYP2C19, CYP2C9, and CYP2B6. CYP2C19 enzyme is one of the important factors related to the clopidogrel activation process, and any mutation of the CYP2C19 gene could decrease the anti-platelet activity of clopidogrel.[4]

Seven articles[567891011] reported data for the CYP2C19 gene variation among Arab people, and some of these articles correlate the gene variations with clopidogrel anti-platelets activity. Eight hundred and sixty-two participants were genotyped in order to determine the CYP2C19 gene status among the Arab populations including Saudis, Egyptians, Jordanians, Lebanese, and Tunisians people. There were 197 participants (22.85%) carrying CYP2C19*2 allele, 230 participants (26.68%) carrying CYP2C19*17 allele and few participants (1.04%) were carrying CYP2C19*3 allele. The mean ADP-induced platelet activation (AIPA) among participants that carrying two wild-type alleles of the CYP2C19 gene was 37.1% ± 23% and was 63.2% ± 33% and 58.29% ± 28% among CYP2C19*2 allele and CYP2C19*3 carriers, respectively.

The most frequent CYP2C19 genotypes found among Arab people were (*1/*1), (*1/*17), (*1/*2), (*2/*2), (*17/*17), (*3/*3) and (*1/*3), respectively [Figure 1]. The AIPA levels were elevated among patients with (*1/*2), (*2/*2), (*3/*3), and (*1/*3) genotypes compared with patients with other genotypes, and the AIPA levels differences between them were significant.

Figure 1

Different CYP2C19 genotypes frequencies among Arab people

The frequency of CYP2C19 (*1/*1) genotype was high as expected; of which 49.4% of the Arab participants included in this study were carrying two wild-type alleles of CYP2C19 gene, thus (*1/*1) genotype described as the most frequent genotype among Arab people. The second most frequent genotype distributed among Arabs was the (*1/*17) genotype; in which 21.2% of the participants carrying this genotype in their genetic makeup. Moreover, CYP2C19 (*1/*2) genotype frequency among Arab participants was 16.7%; which was regarded as the third most frequent genotype among Arab participants. The other highly frequent genotypes among Arab participants including (*2/*2), (*17/*17), (*3/*3), and (*1/*3) with the percentages 6.14%, 5.45%, 0.7%, and 0.35%, respectively.

Based on different CYP2C19 genotypes frequencies data, the most frequent CYP2C19 phenotype among Arab people was the normal CYP2C19 enzyme activity (NCEA); of which 49.4% have this phenotype. Other very common CYP2C19 phenotypes among Arab people include potent CYP2C19 enzyme activity (PCEA) and low CYP2C19 enzyme activity (LCEA) with percentages of 21.2% and 17.05%, respectively.

Nevertheless, some CYP2C19 phenotypes were described as common phenotypes among Arab participants including inactive CYP2C19 enzyme (ICE) and very PCEA (VPCEA) with percentages of 6.84% and 5.45%, respectively. There were significant differences between the NCEA phenotype compared with other phenotypes frequencies related to the CYP2C19 gene (P < 0.0001). Moreover, there were significant differences between PCEA phenotype compared with ICE and VPCEA phenotypes frequencies (P < 0.0001), and also there were significant differences between LCEA phenotype compared with ICE and VPCEA phenotypes frequencies (P < 0.0001). However, there was no significant difference between PCEA and LCEA phenotype frequencies (P > 0.05), and there was no significant difference between ICE and VPCEA phenotype frequencies (P > 0.05).

Conclusions

CYP2C19 genotypes include (*1/*1), (*1/*2), (*1/*3), (*1/*17), (*2/*2), (*3/*3), and (*17/*17) are distributed among Arab population

The AIPA levels were elevated among clopidogrel users with LCEA/ICE phenotypes compared with patients with NCEA phenotype, and the AIPA levels differences between them were significant

The most frequent CYP2C19 genotypes found among Arab people are (*1/*1), (*1/*17), (*1/*2), (*2/*2), (*17/*17), (*3/*3), and (*1/*3), respectively

The most frequent CYP2C19 phenotypes found among Arab people are NCEA, PCEA, LCEA, ICE, and VPCEA, respectively.

Recommendations

Arab patients with CVDs should do CYP2C19 genotyping tests when considering clopidogrel anti-platelet therapy for them

Arab patients who have (*1/*1), (*1/*17) or (*17/*17) genotype could use clopidogrel 75 mg as a maintenance dose, unless if they have any contraindication for clopidogrel

Arab patients who have (*1/*2), (*1/*3), (*2/*2), or (*3/*3) genotype should not use clopidogrel as prophylaxis for CVDs

Patients should be advised to not taking clopidogrel with omeprazole, esomeprazole, lansoprazole, or dexlansoprazole at the same time, and should separate taking them by at least 6–12 h

Patients should be advised to not taking clopidogrel with CYP2C19 enzyme inhibitors (e.g., ketoconazole, fluconazole, fluoxetine, fluvoxamine, oxcarbazepine, topiramate, and isoniazid).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.