Correlation Between Genetic Polymorphisms And Antiplatelet Drug Resistance In Patients With Cerebral Infarction

Objective:To investigate the correlation of aspirin-related and clopidogrel-related gene polymorphisms with aspirin resistance(AR),clopidogrel resistance(CR)and clinical outcomes in patients with cerebral infarction.Methods:A total of 490 patients with cerebral infarction who were admitted to the Department of Neurology,Xinhua Hospital Affiliated to Medical School of Shanghai Jiaotong University from January 2017 to January 2018 were selected.Among them,272 patients took aspirin and 218 patients took clopidogrel during hospitalization.The platelet aggregation inhibition rate was measured by thromboelastograph 7 days after taking aspirin or clopidogrel.The platelet aggregation inhibition rate induced by arachidonic acid(AA%)<50%was diagnosed as AR,and the platelet aggregation inhibition rate induced by adenosine diphosphate(ADP%)<30%was diagnosed as CR.The single nucleotide polymorphisms(SNPs)of aspirin-related genes(GPIIIa,COX-1and PEAR1)and clopidogrel-related gene(CYP2C19)were genotyped by fluorescent probe quantitative PCR.Baseline data such as age,gender,platelet count,low-density lipoprotein level,risk factors for cerebrovascular disease,past medical history,and combined medication were collected.The patients were followed up for 12 months.The end points of follow-up was ischemic vascular events(including vascular death,non-fatal cerebral infarction and myocardial infarction).The patients were divided into wild group,mutant heterozygous group and mutant homozygous group according to genotype.To compare the baseline data between the three groups,and to explore the correlation of their genotypes with AR,CR and clinical prognosis in patients with cerebral infarction.Results:After 12 months of telephone follow-up,the patients who lost the interview,changed the antiplatelet therapy and stopped using antiplatelet drugs were excluded.At last,229 patients who took aspirin and 162 patients who took clopidogrel were included in the data analysis:(1)229 patients with cerebral infarction who took aspirin were genotyped,and their minimal alleles were analyzed.The frequencies were as follows:GPIIIa gene rs5918 locus(0.4%),COX-1 gene rs10306114 locus(0.0%),PEAR1 gene rs12041331 locus(38.2%).The frequencies of the above three SNPs genotypes conformed to Hardy-Weinberg’s law of genetic balance(P>0.05),with group representative.Due to the extremely low probability of gene mutations in the two SNPs of the GPIIIa gene rs5918 locus and the COX-1 gene rs10306114 locus,the patients were divided into three groups according to the genotype of PEAR1 gene rs12041331locus:wild group,mutant heterozygous group and mutant homozygous group.There was no statistical difference in baseline data among the three groups(P>0.05).The AA-induced platelet aggregation inhibition rate(AA%)was compared between the three groups:The median of AA%in wild group,mutant heterozygous group and mutant homozygous group were 88.8%,88.0%and 85.6%,respectively.There was no significant difference among the three groups(P>0.05).The risk of AR among the three groups was compared:among 229 patients,27(11.8%)had AR.The incidence of AR in wild group,mutation heterozygous group and mutation homozygous group was11%,10.5%and 15.5%respectively.There was no significant difference(P>0.05).Kaplan-Meier analysis of PEAR1 rs12041331 genotype and endpoint event showed that there was no correlation between rs12041331 mutation allele(A)and the incidence of endpoint event(P>0.05).(2)162 patients with cerebral infarction treated with clopidogrel were genotyped.The minimum allele frequencies were CYP2C19*2(36.7%),CYP2C19*3(5.2%)and CYP2C19*17(1.2%).The frequencies distribution of the above three SNPs genotypes conform to Hardy-Weinberg’s law of genetic balance(P>0.05),with group representative.In this study,CYP2C19*17 mutations were rare.According to the genotypes of CYP2C19*2 and CYP2C19*3,the patients were divided into three groups:wild group(*1/*1),mutation heterozygous group(*1/*2,*1/*3)and mutation homozygous group(*2/*2,*2/*3,*3/*3).There was no statistical difference in baseline data among the three groups(P>0.05).The ADP-induced platelet aggregation inhibition rate(ADP%)among the three groups was compared:the average value of ADP%in wild group,mutation heterozygous group and mutation homozygous group were 66.05%,58.36%and 47.54%respectively,with significant difference(F=5.861,P=0.003).Comparing the risk of CR among the three groups:19 of 162patients with cerebral infarction(11.7%)had CR.The incidence of CR in wild group,mutation heterozygous group and mutation homozygous group were 5.8%,10.7%and26.9%respectively.The difference was statistically significant(χ~2=6.686,P=0.035).Kaplan-Meier survival analysis of CYP2C19 genotype and endpoint event showed that there was no correlation between carrying CYP2C19*2 or*3 mutation allele(A)and the incidence of endpoint event(P>0.05).Conclusions:(1)Single nucleotide polymorphisms of GPIIIa gene rs5918 and COX-1gene rs10306114 are extremely rare.There is no significant correlation between single nucleotide polymorphisms at rs12041331 locus of PEAR1 gene and AR or clinical prognosis in patients with cerebral infarction.(2)CYP2C19*17 is relatively rare in Chinese population,and its correlation with clopidogrel resistance needs to be further clarified;carrying CYP2C19*2 or*3 mutation allele can weaken the efficacy of clopidogrel and lead to CR,but it is not yet supported to be associated with ischemic vascular events.