Journal Article

Clopidogrel responder status is uninfluenced by CYP2C192 in Danish patients with stroke

Rath, Charlotte Lützhøft, Wienecke, Troels, Jørgensen, Niklas Rye

2020

Overview

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). 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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Adenosine diphosphate / Aged / Alleles / Biology and Life Sciences / Blood platelets / Cardiovascular disease / Clopidogrel / Clopidogrel - therapeutic use / Cytochrome P-450 CYP2C19 - genetics / Denmark / Deoxyribonucleic acid / DNA / Dosage and administration / Drug dosages / Drug therapy / Enzymes / Expected values / Female / Gene Frequency / Genetic analysis / Genetic transformation / Genotype / Hospitals / Humans / Ischemia / Ischemic Stroke - genetics / Ischemic Stroke - prevention & control / Liver / Male / Medicine and Health Sciences / Metabolism / Metabolites / Middle Aged / Mutation / Nucleotides / Observational studies / Oxidation / Patient outcomes / Patients / Platelet Aggregation Inhibitors - therapeutic use / Platelets / Polymorphism, Single Nucleotide / Receptors / Research and Analysis Methods / Secondary Prevention / Single-nucleotide polymorphism / Stroke / Stroke (Disease)