Influence of CYP450 Enzymes, CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention

Chen

et al. 2020

BMC Pharmacol Toxicol

Background: Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China.Methods: One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected.Results: The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77-25.04; p = 0.005); 22.74(95% CI, 3.11-166.27; p = 0.002); 5.69 (95% CI,1.06-30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chen

et al. 2020

BMC Pharmacol Toxicol

“…The P2RY12 receptor plays a key role in the clopidogrel antiplatelet process [36]. The presence of polymorphisms of P2RY12 has failed previously to predict clinical outcomes of clopidogrel therapy [6,32,33]. We verified that mRNA 3ʹ-UTR of P2RY12 is the target of miR-605 through dual luciferase reporter gene analysis.…”

Section: Discussionmentioning

confidence: 78%

“…CYP2B6 mediates two successive oxidation reactions of clopidogrel in the liver, as does CYP2C19 [9]. However, no clear association was previously found between genetic polymorphisms of CYP2B6 and long-term pharmacodynamics or clinical outcomes of clopidogrel therapy [30][31][32][33]. Since CYP2B6 exhibits up to a 250-fold difference in expression variability between individuals [34], its expression level may affect clopidogrel clinical treatment efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…The CYP2C19*2 and CYP2C19*3 LOF polymorphisms result in the loss of CYP2C19 enzyme activity and reduced conversion of clopidogrel to its active metabolite [42,43]. A series of clinical studies have also discovered that the OR for major cardiovascular events is much higher among carriers such as CYP2C19 LOF alleles (CYP2C19*2 and CYP2C19*3) than among non-carriers [6,7,13,32,33].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

microRNA-605 rs2043556 polymorphisms affect clopidogrel therapy through modulation of CYP2B6 and P2RY12 in acute coronary syndrome patients

Zhou

Xiao

et al. 2019

Platelets

Influence of Genetic and Epigenetic Factors of P2Y12 Receptor on the Safety and Efficacy of Antiplatelet Drugs

Danielak

Pawlak

Główka

et al. 2022

Cardiovasc Drugs Ther

Purpose P2Y12 receptor inhibitors are drugs that decrease the risk of stent thrombosis and lower the long-term risk of non-stent-related myocardial infarction and stroke. They inhibit the binding of adenosine diphosphate (ADP) to the P2Y12 receptor and effectively reduce platelet reactivity. However, considerable variability in the pharmacodynamics response contributes to a failure of antiplatelet therapy; this phenomenon is especially notorious for older drugs, such as clopidogrel. Some genetic polymorphisms associated with these drugs’ metabolic pathway, especially in the CYP2C19 gene, can significantly decrease antiplatelet efficacy. There are few reports on the variability stemming from the target of this drug class that is the P2Y12 receptor itself. Results and conclusion This review summarizes the results of research that focus on the influence of P2Y12 genetic polymorphisms on the pharmacodynamics and the efficacy of P2Y12 inhibitors. We found that the conclusions of the studies are unequivocal, and despite several strong candidates, such as G52T (rs6809699) or T744C (rs2046934), they may not be independent predictors of the inadequate response to the drug. Most probably, P2Y12 genetic polymorphisms contribute to the effect exerted by other gene variants (such as CYP2C19*2/*3/*17), drug interactions, or patient habits, such as smoking. Also, epigenetic modifications, such as methylation or miRNA levels, may play a role in the efficacy of antiplatelet treatment.