Polymorphism Distribution Of Clopidogrel Metabolism Related Genes In ACS Patients And Its Relationship With Recent Clinical Endpoints

Part1Distribution of clopidogrel metabolism related gene polymorphisms among Chinese ACS patientsObjective:To detect distribution clopidogrel metabolism related gene polymorphisms CYP2C19, ABCB1and PON1in Chinese ACS patients.Methods:Patients admitted to Fuwai Hospital from2005to2008with ACS within4weeks (30days) were enrolled. All had informed consents for gene samples. The detection of gene polymorphisms was performed by Taqman Systems through PCR-RFLP. The alleles genotyped were CYP2C19*2-*8,*17, ABCB1and PON1. Patients were classified as one of the5categories by metabolizer phenotypes as Extensive [without any "loss-of-function"(LOF) allele*2-*8or "gain-of-function"(GOF) allele*17], Intermediate (with only one LOF allele), Poor (with two or more LOF alleles), Ultra (with one or two GOF alleles) or Unknown (with one LOF allele and one GOF allele).Results:A total of2800Chinese ACS patients were enrolled with age of59.0＋12.3years and79.9%males. The diagnosis proportion were STEMI in74%enrolled patients, NSTEMI in22.0%and UA in4.0%. The minor allele frequency (MAF) for each genotype of CYP2C19*2,*3,*4,*17were28.7%,4.6%,0.1%and1.2%, respectively. No LOF allele*5-*8were found in this population. The MAF for ABCB1and PON1Q192R were39.4%and37.8%. Patient clopidogrel metabolizer groups were defined as Extensive in41.7%enrolled patients, Intermediate in45.6%, Poor in10.3%, Ultra in1.9%and Unknown in0.6%, respectively. There were no significant differences for all genotypes between males and females. Total LOF carriers of CYP2C19were56.4%and GOF carriers were2.5%.Conclusions:Our study reflected the distribution of CYP2C19, ABCB1and PON1gene polymorphisms in Chinese ACS patients. Compared to the Caucasians, it seems LOF genotypes of CYP2C19alleles more common in Chinese. Further exploration is needed to clarify the relation between genotypes and clinical outcomes in Chinese patients. Part2Clinical characteristics of enrolled patientsObjective:To explore baseline characteristics of enrolled patients for association between gene polymorphisms and clinical endpoint.Methods:Ineligible patients (without clopidogrel use during hospitalization、no clinical information and other P2Y12antagonists during hospitalized) were excluded according to exclusion criteria and clinical endpoints were determined based on definition of all clinical events to analyze baseline characteristics of enrolled patients briefly. Results:A total of231patients fulfilled exclusion criteria and were excluded,2569patients entered this part of study about impact of different gene polymorphisms on short-term prognosis eventually. Among them485females (18.9%), median age58years,1431patients (55.7%) with history of hypertension,841patients (32.7%) with history of CHD,639patients (24.9%) with history of diabetes,904patients (35.2%) with history of hyperlipidemia,215patients (8.4%) with history of stroke,2390patients (93.0%) for beta-blocker use,2086patients (81.2%) for ACEI/ARB use,689patients (26.8%) for calcium channel blocker use,2484patients (96.7%) for nitrate use,2470patients (96.1%) for statins use,1689patients (65.7%) diagnosed as STEMI,880patients diagnosed as NSTE-ACS,1644patients (64.0%) underwent PCI,125patients (4.9%) underwent CABG. For clinical events, there were34patients for death,27patients for myocardial infarction,5patients for stent thrombosis, 11patients for repeated revascularization,5patients for stroke,59patients for recurrent angina.Conclusions:Patients enrolled in our study were similar to related study in western countries, only females were less as well as most patients of our study were Chinese population. Part3Association between CYP2C19gene polymorphisms and short-term clinical endpoints of Chinese ACS patientsObjective:To investigate associations between clopidogrel metabolism related genes CYP2C19*2、*3、*4、*17and short-term adverse clinical endpoints like death、myocardial infarction and stent thrombosis among Chinese patients with ACS (acute coronary syndrome).Methods:Based on previous parts about genotyping results and prespecified inclusion and exclusion criteria, we collected clinical information of enrolled patients such as age, gender, past history of disease, in-hospital medications and reperfusion methods, then combined them with gene results to analyze associations between different gene polymorphism and short-term ischemic clinical events like death, myocardial infarction, stent thrombosis. First we analyze impact of single gene on single clinical endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina, subsequently we integrate CYP2C19*2-*4as a whole gene (CYP2C19LOF gene) to evaluate associations between CYP2C19LOF gene and single clinical endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina. We use Cox regression models as statistical methods and the results were presented as HR as well as95%confidence intervals.Results:2569patients entered this part of study about impact of different gene polymorphisms on short-term prognosis eventually. Among them485females (18.9%), median age58years. Multivariable regression models had disclosed only CYP2C19*3and*4were associated with repeated revascularization (HR8.86,95%CI1.76-44.76and HR0.003,95%CI0.000-0.13). CYP2C19*17was not associated with risk of bleeding, other genes were not associated with single endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (all with P>0.05). CYP2C19LOF gene were not associated with single endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (all with P>0.05).Conclusion:There were no significant associations between clopidogrel metabolism related genes CYP2C19*2、*3、*4、*17and short-term adverse clinical endpoints like death, myocardial infarction and stent thrombosis. Only CYP2C19*3and*4were associated with repeated revascularization. These results reminded us that there were no associations between gene polymorphisms and short-term ischemic clinical endpoint, routine genotyping of above genes are not recommended in clinical practice. Part4Association between ABCB1、PON-1gene polymorphisms and short-term clinical endpoints of Chinese ACS patientsObjective:To investigate associations between clopidogrel metabolism related genes ABCB1C3435T and PON-1Q192R and short-term adverse clinical endpoints like death、myocardial infarction and stent thrombosis among Chinese patients with ACS (acute coronary syndrome).Methods:Based on previous parts about genotyping results and prespecified inclusion and exclusion criteria, we collected clinical information of enrolled patients such as age, gender, past history of disease, in-hospital medications and reperfusion methods, then combined them with gene results to analyze associations between different gene polymorphism and short-term ischemic clinical events like death, myocardial infarction, stent thrombosis. First we analyze impact of single gene on single clinical endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina, subsequently we integrate CYP2C19、ABCB1and PON-1as a whole gene to evaluate associations between CYP2C19LOF gene and single clinical endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina, last we evaluate associations between multiple genes and single clinical endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina. We use Cox regression models as statistical methods and the results were presented as HR as well as95%confidence intervals.Results:2569patients entered this part of study about impact of different gene polymorphisms on short-term prognosis eventually. Among them485females (18.9%), median age58years. Multivariable regression models had disclosed only ABCB1associated with composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (HR1.97,95%CI1.09-3.55), other genes were not associated with single endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (all with P>0.05) CYP2C19、ABCB1and PON-1LOF gene were not associated with single endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (all with P>0.05). Multiple genes were not associated with single endpoint and composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina (all with P>0.05).Conclusion:There were no significant associations between clopidogrel metabolism related genes ABCB1C3435T and PON-1Q192R and short-term adverse clinical endpoints like death, myocardial infarction and stent thrombosis. Only ABCB1associated with composite endpoint of death, myocardial infarction, stroke, stent thrombosis, repeated revascularization and recurrent angina. These results reminded us that ABCB1can predict short-term risk of MACE.