The Association Between Clopidogrel Metabolism Gene Polymorphism And Its Antiplatelet Effects

Objecive:Firstly,to detect the single nucleotide polymorphisms of CYP2C19 *2,*3and PON1 Q192 R related to clopidogrel metabolism in ACS patients by genotype analysis.Secondly,to explore relationships between clopidogrel metabolism related gene polymorphisms and its antiplatelet efficacy.Finally,to detect influence factors that can result in clopidogrel resistance.Methods:The 7793 patients were collected retrospectively form 2007 and 2016.Totally,1254 cases of patients match the inclusion and exclusion standard.Firstly,the gene information of 1254 patients admitted to the study was collected and the genetypy frequency and MAF of every allele were calculated and compared with the1000 Genomes Project.Then,gather the platelet aggregation rates induced by ADP that tested five days after taking standard-dose clopidogrel and detect the difference among different CYP2C19 phenotypes or different PON1 Q192 R genetypes after that.Finally,divide the study population into two groups(clopidogrel resistance group and non clopidogrel resistance group)according to the platelet aggregation rate(>50% or not),and then assess the basic clinical information and gene difference between two groups.Results:The MAF of CYP2C19*2,*3 and PON1 Q192 R are 30.62%,5.2% and37.00% respectively.The phenotypes of CYP2C19 include extensive metabolism(41.07%),intermediate metabolism(44.98%)and poor metaolism(13.96%).PON1Q192 R was divided into high expression type(GG),intermediate expression type(GA) and low expression type(AA),each accounted for 39.15%,47.69% and13.16%.Finally,when we compared the CR and NCR groups,the combined medicine has no difference between the two groups(P>0.05).As for the comorbidities,DM and hyperlipermia have no impact on clopidogrel resistance(P>0.05),but the incidence of stroke history(1.16%vs0.15%)and hypertension(65.62% vs 59.32%)is remarkablely higher in CR group than NCR groups(P=0.033,P=0.021).At the same time,average age of CR group(59.36±9.81)is much greater than NCR group(57.98±10.06,P=0.014),and women in CR group(33.06%)are much more than NCR group(26.35%,P=0.009).The CYP2C19*2 and *3 MAF difference is significant(P=0.000),other than PON1 Q192 R.Finally,we compared the genetype frequency of each allele between two groups,every genetype of CYP2C19*2 and *3has statistical difference between two groups,only AA and GG genetype of PON1Q192 R,however,show significant difference between CR and NCR groups(P=0.002,P=0.008),the distribution of GA in the two groups indicated meaningless difference(P=0.611).Conclusion:There is no significant difference between the MAF of each allele in the study and the 1000 Genomes Project,so that the study population can represent the Han Chineses.Gene polymorphism of CYP2C19*2,*3 and PON1 Q192 R can exercise great influences on the clopidogrel efficacy in Chinese ACS patients.And the CYP2C19 LOF gene can enhance degradation of clopidogrel efficacy resulted from PON1 Q192 R mutant gene.At last,we found that female,advanced age hypertension and stroke history might be risk factors for clopidogrel resistance except gene polymorphism.As for clopidogrel metabolism related genes,the gene mutantion of CYP2C19*2 and *3 have much more risk than PON1 Q192 R.And for PON1 Q192 R allele,the patients carrying homozygous of the mutant gene obtain more risk to have clopidogrel resistance than heterozygotes.