Neurovascular Centre, Department of Neurology, Zealand University Hospital, Roskilde, Denmark.
Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2020 Dec 28;15(12):e0236260. doi: 10.1371/journal.pone.0236260. eCollection 2020.
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, CYP3A41G, 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.
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, CYP3A41G, and NR1I2 revealed no associations with clopidogrel HTPR. CYP2C192 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.
抗血小板治疗是二级预防卒中的基石，但患者对抗血小板药物的反应存在差异。氯吡格雷是一种前体药物，需要在肝脏中转化为其活性代谢物。血小板表面的关键酶或靶腺苷二磷酸（ADP）受体上的单核苷酸多态性（SNP）被认为与氯吡格雷介导的血小板抑制和高治疗血小板反应性（HTPR）相关的抗血小板作用降低有关。
本研究旨在探讨关键肝酶（CYP2C19*2、*3、17、CYP3A41G 和 NR1I2）或 ADP 受体（PR2Y12）中的特定 SNP 是否与氯吡格雷的 HTPR 相关。
本观察性研究纳入了接受氯吡格雷 75mg/天治疗的缺血性卒中和短暂性脑缺血发作（TIA）患者。对编码 CYP2C19、CYP3A4、NR1I2 和 P2Y12 受体的基因中的 8 种不同 SNP 进行了基因分型。
在纳入的 103 例患者中，30.7%携带 CYP2C192 等位基因，血小板反应单位（PRU）值高于非携带者，但无患者出现 HTPR。携带17 等位基因的患者血小板抑制作用较高，但 PRU 值与非携带者无差异。其余 SNP 既与 PRU 也与血小板抑制无关。
接受 75mg 氯吡格雷/天治疗的缺血性卒中和 TIA 患者不存在 HTPR。对 CYP2C19*2、3、17、CYP3A41G 和 NR1I2 的基因分析未发现与氯吡格雷 HTPR 相关。CYP2C192 携带者和缺血性卒中和 TIA 后急性期 HTPR 患者的 PRU 值较高，但长期治疗 HTPR 不存在。
