Clopidogrel responder status is uninfluenced by CYP2C19*2 in Danish patients with stroke

Abstract

Background Antiplatelet therapy is a cornerstone of secondary stroke prevention, but the responsiveness to antiplatelet medication varies among patients. Clopidogrel is a pro-drug that requires hepatic transformation to reach its active metabolite. Single nucleotide polymorphisms (SNPs) in key enzymes or the target adenosine diphosphate (ADP) receptor on the platelet surface are believed to be involved in clopidogrel-mediated platelet inhibition and decreased antiplatelet effect with high-on-treatment platelet reactivity (HTPR). Objective This study investigated whether specific SNPs in key hepatic enzymes (CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2) or the ADP receptor (PR2Y12) are associated with HTPR to clopidogrel. Patients & methods This observational study included patients with ischemic stroke (IS) and transient ischemic attacks (TIAs) receiving clopidogrel at a dose of 75 mg/day. Patients were genotyped for eight different SNPs in the genes encoding CYP2C19, CYP3A4, NR1I2, and the P2Y12 receptor. Results Of the 103 patients that were included, 30.7% carried the CYP2C19*2 allele and had higher platelet reaction unit (PRU) values than non-carriers, but no patients showed HTPR. Carriers of the *17 allele had higher platelet inhibition but showed no difference in PRU values compared with non-carriers. The remaining SNPs were neither associated with PRU nor with platelet inhibition. Conclusions Patients with IS and TIAs treated with 75 mg clopidogrel/day do not have HTPR. A genetic analysis of CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2 revealed no associations with clopidogrel HTPR. CYP2C19*2 carriers and patients with HTPR in the acute phase after ischemic stroke or transient ischemic attacks exhibit higher PRU values, but not long-term treatment HTPR.

A Pharmacogenetic Study of CYP2C19 in Acute Coronary Syndrome Patients of Colombian Origin Reveals New Polymorphisms Potentially Related to Clopidogrel Therapy

“…It is administered as an inactive prodrug that requires hepatic conversion by cytochrome P450 (CYP) enzymes, mainly 2C19 to produce an active metabolite [ 6 ]. CYP2C19 polymorphisms are related to the anti-platelet effects of clopidogrel [ 4 , 7 , 13 , 24 ]. To the best of our knowledge, this study is the first to assess the variants of the promoter region, the intronic and coding region of CYP2C19 through sequencing in a group of Colombian patients with ACS and determines the association with platelet reactivity.…”

“…These findings have justified the implementation of clinical management guidelines based on genotype, which suggest that new P2Y 12 inhibitors such as prasugrel and ticagrelor are alternatives for patients who are carriers of LOF genetic variants for CYP2C19. Screening for the presence of loss-of-function alleles could allow more informed decision-making regarding the choice of the P2Y receptor blocker [ 15 , 24 , 31 ].…”

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

“…Despite these reports, a number of studies failed to notice any influence of T744C on the prevalence of HTPR or adverse events [ 32 , 34 , 39 , 43 – 50 , 58 , 67 , 68 ]. It is also possible that the effect of T744C on platelet function and the efficacy of clopidogrel treatment may depend on the coexistence of other factors, such as compliance, drug interactions, and comorbidities [ 51 , 69 , 70 ].…”

“…Global allele frequencies (AF) taken from the Ensembl database, 1000 Genomes Project Phase 3 ( ensembl.org ). The alleles leading to a possible function alteration are in bold Accession number Position Common name Region Change AF Modification Function alteration rs6798347 g.1387C > T - Promoter G > A G: 0.711 A: 0.289 Promoter modification Possible lower incidence of HTPR (as part of H1 haplotype) [ 32 ] rs1907637 g.2707 T > C - Promoter G > A G: 0.903 A: 0.097 Promoter modification May influence baseline platelet aggregation [ 33 ] rs6787801 g.7804 T > G - Intron T > C T: 0.527 G: 0.473 Intron variant Possible lower incidence of HTPR (as part of H1 haplotype) [ 32 ] rs9859552 g.16549C > T - Intron G > T G: 0.938 T: 0.062 Intron variant Noticeable but not significantly greater platelet reactivity [ 34 ] rs3732759 g.32620 T > C - Intron A > G A: 0.678 G: 0.322 Intron variant Occurs more frequently in patients with CVD rs7428575 …”

Relationship between recurrent ischemic events in cerebrovascular disease and cytochrome P450 2C19 gene polymorphism on the basis of thrombelastography

“…Statistics show that China's annual number of new strokes is 1.5-2 million, the annual incidence is 116-219/100,000, and annual mortality is 58-42/100,000, making stroke China's leading cause of death. Ischemic stroke usually occurs in people over 50-60 years of age, often with atherosclerosis, hypertension, rheumatic heart disease, coronary heart disease, or diabetes, and smoking, drinking, and other unhealthy lifestyle habits (3)(4)(5). Few ischemic stroke patients are completely cured, and there is a high recurrence rate.…”