除了 CYP2C19*2，CYP2C9*3 变异等位基因与接受择期冠状动脉支架植入术的双联抗血小板治疗患者的氯吡格雷血小板反应性升高相关。
Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation.
机构信息
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
出版信息
Pharmacogenet Genomics. 2010 Jan;20(1):18-25. doi: 10.1097/FPC.0b013e328333dafe.
INTRODUCTION
The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.
OBJECTIVES
To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C92, 3, CYP2C193, CYP3A41B, and CYP3A53), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C192 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.
METHODS
Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day for > or =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.
RESULTS
In both the treatment groups, CYP2C192-carriage was associated with higher platelet reactivity (P<0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C93-carriage was associated with higher platelet reactivity (P<0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).
CONCLUSION
Besides CYP2C192, the variant allele CYP2C93 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.
简介
前药氯吡格雷在接受冠状动脉支架置入术的患者血栓事件预防中发挥着重要作用。然而，仍有大量的动脉粥样硬化血栓事件发生，这部分可以用血小板反应性增强来解释。一些研究表明，CYP2C19 (*2)的遗传变异与氯吡格雷反应受损有关。
目的
评估影响氯吡格雷吸收（ABCB1 C1236T、G2677T/A、C3435T）、代谢（CYP2C92、3、CYP2C193、CYP3A41B 和 CYP3A53）和药效学（P2Y1 A1622G）的基因变异除 CYP2C192 对接受双重抗血小板治疗的择期冠状动脉支架置入术患者血小板反应性的影响。
方法
通过光透射聚集法和 VerifyNow P2Y12 测定法评估 428 例连续患者的血小板功能。患者要么接受慢性氯吡格雷维持治疗（干预前>5 天每天 75mg），要么接受 300mg 氯吡格雷负荷剂量（干预前 1-5 天，随后每天 75mg）。线性和逻辑回归用于评估基因变异与血小板反应性和不良反应者状态之间的关联。
结果
在两个治疗组中，CYP2C192 携带与更高的血小板反应性（P<0.002）和不良反应者状态相关；75mg 组：调整后的比值比（ORadj）：3.8，95%置信区间（CI）：2.0-7.2，300mg 组：ORadj：4.1，95%CI：1.6-10.4。在 300mg 组中，CYP2C93 携带与更高的血小板反应性（P<0.05）和不良反应者状态相关（ORadj：11.1，95%CI：1.6-78.8，P=0.016）。
结论
除 CYP2C192 外，变体等位基因 CYP2C93 在接受双重抗血小板治疗的冠状动脉支架置入术患者中对氯吡格雷的反应中也起着重要作用。
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