Effect Of CYP2C19Polymorphism And Risk Factors For Coronary Artery Disease On Clopidogrel Response Diversity

Background:PCI (percutaneous coronary intervention) has gained substantial success owing to technology and equipment advances in the past decades. Dual antiplatelet therapy with clopidogrel and aspirin is the established treatment for reducing the occurrence of stent thrombosis, which was shown to significantly improve prognosis in patients with coronary heart disease undergoing PCI. However, interindividual variability exists in clopidogrel-iniduced inhibition of platelet aggregation, described as clopidogrel response diversity. Evidence indicates that4%-30%of patients do not achieve adequate antiplatelet effect, who have been labeled as clopidogrel low responders and nonresponders. This finding led to the concept of clopidogrel resistance (CR). These patients may be at higher risk for recurrent adverse cardiovascular events. CRD has emerged as a hot issue recentely. Outcomes of CR patients may be improved through individualized treatment strategies based on better prediction of this phenomenon. CRD can be due to medications, atherosclerotic burden, genetic polymorphisms, or a combination of these and other factors.Clopidogrel is a prodrug, which needs to be metabolized in the liver by cytochrome P450into active metabolites, and irreversibly antagonizes ADP receptor P2Y12on platelet. CYP2C19, a member of CYP450family, whose polymorphism has been found to correlate with impaired metabolism of clopidogrel, leading to CRD. It is reported that nearly100%of poor responders to clopidogrel in Asian carry the allelic genic mutation of CYP2C19. Recent studies also have suggested that patients who are complicated by a higher body mass index (BMI), diabetes mellitus, or smoke tend to have CR. Whether polymorphisms of the clopidogrel combined with these fisk factors play additional roles in modulating the individual response remains to be elucidated, which may provide more information for indentifying CR patients in a high-risk clinical setting such as PCI.Objective:The aim of present study is to investigate an association of responsiveness to clopidogrel with CYP2C19polymorphism and nongenetic factors, to evaluate the relative impact of these factors, and to verify the association between CR and poor prognosis in PCI patients, which may direct individualized antiplatelet strategies in future.MethodsFrom November2010to May2011,145patients undergoing percutaneous coronary intervention in our department were enrolled and received300mg loading dose and75mg daily maintenance dose of clopidogrel. Blood samples were collected and measured1week later:1. Activity of platelet:Clopidogrel resistance was defined as platelet reactivity index (PRI)≥50%, which was measured by flow cytometric assessment of phosphorylation status of vasodilator-stimulated phosphoprotein (VASP).2. Genotype of CYP2C19:According to the missing of allelic gene detected by TaqMan polymerase chain reaction,No.636and No.681base pairs, genotype of CYP2C19was classified as:wild type*1/*1(636GG/681GG), heterozygous mutant type*1/*2(636GG/681GA) and*1/*3(636GA/681GG) and homozygous mutanttype*2/*2(636GG/681AA)、*2/*3(636GA/681GA)、*3/*3(636AA/681GG).3. Logistic regression analysis was used to determine the correlation between CR and CYP2C19genotype, risk factors, such as diabetes mellitus, hypertension, age and so on.4. All the patients were followed up for12months.The primary clinical end points were death, reinfarction, target vessel revascularization, and the secondary clinical end points were stent thrombosis, stroke, and hemorrhoea.Results1. Clopidogrel resistance was present in20.67%patients.2. The number and proportion of wild type(*1/*1) was57and39.31%, respectively, while heterozygous mutant type(*1/*2、*1/*3)69and47.59%, respectively, and homozygous mutant type(*2/*2、*2/*3、*3/*3)19and13.1%, respectively. In patients with homozygous mutant type,2patients (1.38%) carried genotype of*3/*3,4patients(2.76%) carried genotype of*2/*3and13patients (8.97%) carried genotype of*2/*2.3. Patients with homozygous mutant type had significantly higher platelet reactivity than those with wild type and heterozygous mutant type. Mean VASP PRI were49.67±4.91,45.20±7.14,43.73±7.08respectively.4. Independent predictors for CR were were homozygous mutant type (OR:4.43;95%CI:3.28to6.37; P<0.05), diabetes mellitus (OR:2.76;95%CI:2.13to4.14;P<0.05) and BMI (OR:2.01;95%CI:1.63to3.71). Subgroup analysis demonstrated that homozygous mutant type together with diabetes was the best discriminator.5. The clinical follow-up revealed higher incidence of MACE (6.45%vs1.75%, P<0.05)and thrombosis (3.23%vs0.88%,P<0.05) in CR patients.Conclusion1.VASP measured by flow cytometry can be used to determine the extent of clopidogrel-iniduced platelet aggregation inhibition.2.The incidence of CR is higher in patients with homozygous mutant type of CYP2C19than those with other types.3.Homozygous mutant type of CYP2C19, diabetes mellitus and BMI can be used as independent predictive factors, while the combinaion of homozygous mutant type of CYP2C19and diabetes mellitus may provide better prediction.4.The incidence of MACE and stent thrombosis after PCI is higher in CR patients, while CR may forcast poor outcomes in PCI patients.