Angiolillo Dominick J, Fernandez-Ortiz Antonio, Bernardo Esther, Ramírez Celia, Cavallari Ugo, Trabetti Elisabetta, Sabaté Manel, Hernández Rosana, Moreno Raul, Escaned Javier, Alfonso Fernando, Bañuelos Camino, Costa Marco A, Bass Theodore A, Pignatti Pier Franco, Macaya Carlos
Division of Cardiology, University of Florida, Shands Jacksonville, 655 West 8th St, Jacksonville, FL 32209, USA.
Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1895-900. doi: 10.1161/01.ATV.0000223867.25324.1a. Epub 2006 Apr 27.
Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability.
The CYP3A41B, CYP3A43, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation (P=0.025) and better responsiveness (P=0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P=0.025), increased platelet inhibition (P=0.006), and a more optimal drug response (P=0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness.
The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.
细胞色素P450（CYP）3A4的代谢活性与氯吡格雷反应变异性相关。由于CYP3A4的代谢活性受基因调控，我们推测该酶的基因变异可能导致氯吡格雷反应变异性。
在82例处于氯吡格雷治疗稳定期的患者中评估了CYP3A4基因的CYP3A41B、CYP3A43、IVS7+258A>G、IVS7+894C>T和IVS10+12G>A多态性。评估了糖蛋白（血小板糖蛋白（GP）IIb/IIIa受体激活和血小板聚集情况。研究了一组45例未使用过氯吡格雷的患者，以确定在给予负荷剂量（300mg）后这些多态性的调节作用。只有IVS7+258A>G、IVS7+894C>T和IVS10+12G>A多态性具有足够的多态性。在氯吡格雷治疗稳定期，IVS10+12A等位基因携带者的GP IIb/IIIa激活降低（P=0.025）且反应性更好（P=0.02）；同样，未使用过氯吡格雷的患者中，IVS10+12A等位基因携带者在负荷剂量后的最初24小时内GP IIb/IIIa激活降低（P=0.025），血小板抑制增加（P=0.006），药物反应更理想（P=0.003）。该多态性不影响血小板聚集情况。未观察到其他多态性与氯吡格雷反应性之间的关联。
CYP3A4基因的IVS10+12G>A多态性可调节氯吡格雷治疗患者的血小板激活，因此可能导致氯吡格雷反应变异性。
