Institute of Geriatric Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
Thromb Res. 2013 Jul;132(1):81-7. doi: 10.1016/j.thromres.2013.05.006. Epub 2013 May 29.
Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on-treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known.
Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People's Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C192 (rs4244285), CYP2C193 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20 μmol/L adenosine diphosphate (ADP)-induced platelet aggregation>50%.
Both CYP2C19*2 and 3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P<0.00001 and P=0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (2 or 3, accounted for 58% of the study population) was obviously higher than that in non-carriers (P<0.00001). Patients with the CYP2C192 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95% confidence interval(CI), 1.04-2.33, P=0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95% CI: 1.33-2.4,P=0.003). However, the carriage of CYP2C193 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95% CI: 0.83-3, P=0.16). Significant relation of CYP2C1917, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found.
In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients.
细胞色素 P450（CYP）、ATP 结合盒转运蛋白（ABCB1）和对氧磷酶-1（PON1）在氯吡格雷吸收和生物活化中发挥着重要作用。这些基因的遗传多态性与氯吡格雷反应的变异性有关，但它们在中国氯吡格雷治疗患者中的高治疗后血小板反应性（HPR）的贡献尚不清楚。
2010 年 9 月至 2012 年 9 月，连续从中国人民解放军总医院老年心血管科招募了 500 例接受氯吡格雷治疗的急性冠状动脉综合征（ACS）的中国汉族患者。我们评估了 CYP2C192（rs4244285）、CYP2C193（rs4986893）、CYP2C19*17（rs12248560）、PON1Q129R（rs662）和 ABCB1C3435T（rs1045642）与氯吡格雷维持剂量 5 天后血小板聚集的关系，以及发生 HPR 的风险。HPR 的截止值定义为 20μmol/L 二磷酸腺苷（ADP）诱导的血小板聚集>50%。
CYP2C19*2 和 3 等位基因均与氯吡格雷维持剂量 5 天后的血小板聚集明显相关（P<0.00001 和 P=0.042）。至少携带一个 CYP2C19 失活功能等位基因（2 或 3，占研究人群的 58%）的患者血小板聚集明显高于非携带者（P<0.00001）。与 CYP2C19 野生型基因型相比，携带 CYP2C192 等位基因的患者发生 HPR 的风险更高[校正危险比（HR），1.56；95%置信区间（CI），1.04-2.33，P=0.03]。至少携带一个 CYP2C19 失活功能等位基因的携带者与非携带者相比，发生 HPR 的风险显著增加（校正 HR1.79，95%CI：1.33-2.4，P=0.003）。然而，CYP2C193 单独携带并不能显著预测 HPR 的风险（校正 HR，1.5；95%CI：0.83-3，P=0.16）。未发现 CYP2C1917、PON1Q129R 和 ABCB1C3435T 与血小板聚集有显著关系。
在中国 ACS 接受氯吡格雷治疗的患者中，至少携带一个 CYP2C19 失活功能等位基因的患者发生 HPR 的风险更高，其影响主要归因于 CYP2C19*2。ABCB1 或 PON1 基因型均不能影响中国患者氯吡格雷的抗血小板反应。
