Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients

Abstract

Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention

“…Our reports also indicated only homozygous PONQ192R showed attenuated response to clopidogrel therapy. This results are the same as several reports [29,30]. However, other studies could not discovery the influence of PON1 Q192R genotype on clopidogrel induced antiplatelet aggregation inhibition [31,32], This may due to the small effects of PON1 Q192R polymorphism on platelet aggregation.…”

Pharmacogenomics research and clinical implementation in Brazil

“…Figure shows a flowchart of our search results. After filtering PubMed entries and publications from REFARGEN members, 72 articles were selected, 22 of which examined both pharmacogene(s) and drug(s) from a CPIC guideline (Table ). The remaining 50 articles investigated one or more genes comprised in the guidelines.…”

“…The frequency of these alleles does not differ among self‐reported white, brown and black Brazilians (Table ). One article studied CYP2C19 and clopidogrel in the context of the CPIC guidelines . Patients (n = 187) who underwent percutaneous coronary intervention and were under treatment with clopidogrel and/or aspirin were genotyped for the CYP2C19*2 and *3 alleles as well as for polymorphisms in the PON1 gene, which encodes the enzyme paraoxonase‐1, involved in esterification and inactivation of clopidogrel.…”

Research Article RFLP-PCR is more efficient than ARMS-PCR for identifying CYP2C19*2 polymorphism in atherosclerotic patients

“…Clopidogrel requires its conversion into its active metabolite through hepatic mechanisms involving a large amount of CYP450 isoenzymes, among them CYP2C19, responsible for almost half of the phase I detoxification processes (Marchini et al, 2017). At least three alleles have been detected for CYP2C19 isoenzyme and two of them are associated with a loss of function: CYP2C19*2 and *3.…”