The Association Between CYP2C19*2Gene Polymorphisms And Clopidogrel Resistance In The Han Population Of North China With Coronary Atherosclerotic Heart Disease

Objective: The Phenomenon of clopidogrel resistance (CR) is receivingincreasing concern. Due to the diversification of platelet function test and definedcriteria applied in previous studies, there is a big difference in the incidence of CR.Besides, it remains unclear of the mechanisms underlying CR and genepolymorphisms is regarded as an major factor of individual differences of drugresponse. The present study aimed to observe the frequencies of CR in the Hanpopulation of North China with Coronary Atherosclerotic Heart Disease (CAHD)and at the genetic point of view, to elucidate the preliminary association betweenCYP2C19*2(Cytochrom P4502C19,CYP2C19*2) gene polymorphisms thatplays an important role in clopidogrel biotransformation to its active form and CR.We further aimed to provide evidence on the early predication of CR andimplement of individualized and rationalized drug therapy when a variety of newantiplatelet drugs were available nowadays.Methods:136patients with angiographically documented CAHD in the Hanpopulation of North China were consecutively enrolled from Mar.2011toFeb.2012in the General Hospital of Chinese People's Armed Police Forces. Thevasodilator-stimulated phosphoprotein (VASP) phosphorylation state wasdetermined by flow-cytometry in all patients received a600mg loading dose ofClopidogrel. Patients enrolled were divided into CR group and Non-CR(Non-clopidogrel resistance, NCR) group according to the value of VASP index.A VASP index of≧50%was regarded as CR. The presence of CYP2C19*2polymorphisms was determined by polymerase chain reation-restriction fragmentlength polymorphism (PCR-RFLP) analysis combined with sanger dideoxymediated chain termination method. The VASP index values were comparedamong the individuals with the different genotypes, in addition, the distribution of the frequencies of genotypes and alleles among CR and NCR groups wasanalyzed.Results: There were148patients in the initial screening stage, then twelvecases were excluded (Two cases with oral administration of clopidogrel in twoweeks prior to enrollment, four cases without coronary angiography, two casesrefused to receive genetics testing, two cases for PCR fails and two did notreceive flow cytometry analysis for occurrence of haemolysis). Finally, a total of136patients (73with Acute Coronary Sydrome and60with Stable AngianPectoris) were enrolled, and among them,60cases underwent elective PCI.1Basic characteristics between CR group and NCR group Demographicand Clinical characteristics including age, gender, history of Hypertention,Dyslipidemia, concurrent medications, such as Stains, Calcium channel blockers,Proton pump inhibitors, did not differ between the two study groups(P>0.05).When compared with the NCR group, the proportion of Overweight,Type2Diabetes mellitus and ACS were significantly higher in the CR group(P<0.05) while the proportion of smokers were significantly higer in the NCRgroup (P<0.05).2Incidence of CR Accroding to the present study, there were80patitensin the CR group and56patients in the NCR group, indicating the occurrence ofCR at a rate of58.82%. The occurrence of CR were at a rate of67.12%(49patients) and51.67%(31patients) among patients with Acute CoronarySydromes (ACS) and Stable Angian Pectoris (SAP), respectively. Compared withSAP, patients with ACS were at a higher rate of occurrence of CR (P<0.05).3Comparison of distribution of the frequencies of genotypes (GG/GA/AA)and alleles between CR and NCR groups3.1The CYP2C19*2gene polymorphisms was in Hardy-Weinbergequilibrium (P>0.05).3.2The VASP index values were (47.73±15.34)%,(56.78±14.49)%and(67.74±14.05)%among the individuals with the genotype of GG, GA and AA,respectively. Statistically significant difference was observed using analysis ofvariance (P<0.001). Further adoption of LSD-t test was used for multiple comparisons. Compared with the patients with GG genotype, patients with GAand AA genotype displayed significantly higher VASP index value (P<0.05)；Patients with AA genotype displayed significantly higher VASP index value thanGA genotype(P<0.05).3.3The genotype (GG/GA/AA) distribution of the CYP2C19*2genepolymorphisms were47.54%,46.22%,6.24%and69.63%,26.80%,3.57%in theCR and NCR groups, respectively. Statistically significant difference wasobserved between CR and NCR groups for distribution of the genotypes (P<0.05).Frequency of AA genotype was significantly higher in CR group than in NCRgroup (P<0.05), Frequency of A allele was significantly higher in CR group thanin NCR group (29.37%vs16.96%, P<0.05), A allele carriers were more likely todevelop CR (OR=2.04,95%CI:1.12-3.71, P<0.05). Binary logistic regressionanalysis adjusted for the presence of traditional risk factors including Age, Gender,BMI, Smoking, Hypertention, Dyslipidemia, Type2Diabetes, the CYP2C19*2polymorphism resulted an independent risk factor for CR(OR=3.259,95%CI:1.23-4.19, P<0.05).Conclusion: The occurrence of CR is a common phenomenon in the Hanpopulation of North China with CAHD at a rate of58.82%. CYP2C19*2genepolymorphism is associated with the occurrence of CR; CYP2C19*2, that is tosay, A allele might be an important genetic risk factor for the development of CR.