细胞色素P450 2C19基因多态性与急性冠脉综合征患者PCI治疗后血小板再活化及预后的关系

Effects of cytochrome P450 2C19 genetic polymorphism on high post-treatment platelet reactivity and prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention

目的探讨细胞色素P450 2C19(CYP2C19)基因多态性与接受经皮冠状动脉腔内介入(percutaneous coronary intervention,PCI)治疗的急性冠脉综合征(acute coronary syndrome,ACS)患者术后血小板再活化(posttreatment platelet reactivity,HPPR)的关系及对其临床预后的影响。方法选择2011年1月至2012年6月在广州市第一人民医院心内科住院,诊断为ACS并接受PCI治疗的患者362例。于PCI治疗后测定5μmol/L腺苷二磷酸(ADP)诱导的血小板聚集率(platelet aggregation ratio,PAR),以受试者工作曲线(ROC曲线)确定预测患者术后主要心血管事件(major adverse coronary event,MACE)发生的最佳PAR值(44.5%)后将患者分为HPPR组(PAR≥44.5%)和对照组(PAR<44.5%)。应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)检测患者CYP2C19基因681(G/A)位点的基因型和等位基因,观察两组患者CYP2C19(681G/A)基因型、等位基因分布情况及住院期间与术后6个月随访期内MACE的发生情况。结果 HPPR组CYP2C19(681AA)基因型及携带681A等位基因频率均显著高于对照组,差异有统计学意义(25.9%vs.10.4%,P<0.01;48.7%vs.24.0%,P<0.01)。HPPR组明确的支架血栓事件及随访期间MACE的发生率均高于对照组,差异有统计学意义(5.3%vs.0.8%,χ2=7.433,P=0.012;14.3%vs.7.2%,χ2=4.563,P=0.047)。多因素Logistic回归分析结果显示携带CYP2C19(681A)基因、HPPR均是ACS患者PCI治疗后MACE发生的独立预测因子(P<0.05)。结论 ACS患者CYP2C19基因681(G/A)位点单核苷酸多态性与PCI治疗后HPPR存在相关性;ACS患者CYP2C19基因的突变导致患者对抗血小板治疗的低反应性,并增加患者PCI治疗后血栓事件和MACE发生的风险。

Objectives To investigate the relationship between cytochrome P450 2C19（CYP2C19） genetic polymorphism and high post-treatment platelet reactivity（HPPR） in patients with acute coronary syndrome（ACS） undergoing percutaneous coronary intervention（PCI）,and to assess the effect of CYP2C19 genetic polymorphism on the prognosis of patients with ACS. Methods Totally 362 patients with ACS undergoing PCI from January 2011 to June 2012 in The First People ＇s Hospital of Guangzhou were enrolled. The 5 μmol / L adenosine diphosphate（ADP）-induced platelet aggregation ratio（PAR） were measured 12-24 hours after PCI. Patients were divided into control group（PAR 44.5%） and HPRR group（PAR≥44.5%） according to the optimal value of PAR（44.5%,confirmed by receiver-operating characteristic curve） for predicting major adverse cardiac events（MACE）. Genomic DNA of patients were extracted from whole blood samples and polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） method was used to genotype the single nucleotide polymorphism of CYP2C19 681 G / A. After PCI,patients were followed up for 6 months and MACE（including stent thrombosis events） during the period were recorded. Results The frequencies of CYP2C19 and genotype CYP2C19 681 AA in HPPR group were significantly higher than those in control group（25.9% vs. 10.4%,P〈0.01; 48.7% vs. 24.0%,P〈0.01）. Incidence rates of stent thrombosis and MACE during follow-up in HPPR group were also significantly higher than those in control group（5.3% vs. 0.8%,χ^2=7.433,P=0.012; 14.3% vs. 7.2%,χ^2=4.563,P =0.047）. Binary Logistic regression analysis indicated that both gene CYP2C19 681 A and HPPR were strong independent predictors for MACE in patients with ACS after PCI（P〈0.05）. Conclusions Genetic polymorphism of CYP2C19 is associated with HPPR in patients with ACS undergoing PCI. Mutation of CYP2C19 induces the hypoergia to antiplatelet therapy and increases the risk of stent thrombosis and MACE in patients with ACS after PCI.