The Relationship Between Gene Polymorphism With Aspirin Resistance In Recurrent Atherosclerotic Ischemic Stroke

Objective To investigate the relationship of COX enzyme gene,platelet transmembrane glucose protein receptor(GP)gene,ADP receptor(P2Y1 and P2Y12)gene,and TXA2 receptor gene polymorphisms with the recurrence of atherosclerotic ischemic stroke and aspirin resistance,providing a theoretical basis for individualized treatment of antiplatelet therapy in patients with ischemic stroke.Methods By a single-center,prospective cohort study design,from May 2018 to October 2019,we enrolled the patients hospitalized in XX Hospital diagnosed as atherosclerotic ischemic stroke but still relapsed during the period of taking aspirin,and those signed the informed consent were enrolled in the group.All patients' blood routine,biochemical items,coagulation function,blood lipid analysis,homocysteine must be obtained within 24 hours after admission,and the baseline data such as sex,age,body mass index,smoking history,drinking history,hypertension,diabetes,coronary heart disease,atrial fibrillation,cerebral infarction,cerebral hemorrhage,taking aspirin and statins and TOAST classification were collected.19 single nucleotidegene polymorphisms,including COX-1(rs1330344)?GP?b/?a(rs5918)?GP?a/?a(rs1126643?rs1062535)?GP?(rs1613662?rs1671153?rs12610286)?GP?b(rs6065)?TXA2(rs1131882?rs2238634?rs4523?rs4806942)?P2Y12(rs10935838?rs2046934?rs5853517?rs6809699)?P2Y1(rs1371097?rs12497578?rs1439010),were eximained by PCR and gene sequencing.Platelet function was detected by thromboelastography within 24 hours after admission.According to the results of thromboelastogram,the patients were divided into aspirin resistance group and aspirinsensitive group,and the genotypic differences of 19 genes between the two groups were compared.Patients in aspirin sensitive group continued to take aspirin against platelet aggregation,while patients in aspirin resistance group adjusted antiplatelet therapy.All patients were followed up 30 days,90 days and 6 months.The primary endpoint was recurrent stroke,the secondary endpoints were themorrhagic stroke and all-cause death.Results A total of 35 patients were enrolled,including 26 males and 9 females.The age range was 43 to 83 years,and the average age was(68.69 ± 8.30)years.1According to thromboelastography,among the 35 patients,there were 16 patients in aspirin resistant group and 19 patients in aspirin sensitive group.The incidence of AR was 45.71%.There was no significant difference in sex,age,body mass index,drinking history,hypertension,diabetes,coronary heart disease,atrial fibrillation,cerebral infarction,history of cerebral hemorrhage,use of aspirin and statins,TOAST classification,ESSEN,MIHSS,mRS,blood routine,blood lipids,blood coagulation,homocysteine and other indexes between AR group and AS group.However,there was a high proportion of smoking in AR group,the level of fibrinogen in AR group was also higher than that in AS group(3.18±1.47 vs.2.45±0.65,P=0.042).Logistic regression showed that smoking was a risk factor for aspirin resistance(OR=4.904,95%CI=1.020-23.576,P=0.047).2 Some important parameters in thromboelastography,such as R,K value,? angle,MA were not significantly different between the two groups,the AA inhibition rate in the AR group was significantly lower than that in AS group(28.80 ± 14.96 vs77.87 ± 13.58,P <0.0001).3 As GP?b/?a rs5918 genotypes of 35 subjects were all wild-type,statistical tests could not be performed,COX-1(rs1330344)GPIa/IIa(rs1126643,rs1062535),GP?(rs1613662,rs1671153,rs12610286),GP?b(rs6065),TXA2(rs1131882,rs2238634,rs4523,rs4806942),P2Y12(rs10935838,rs2046934,rs5853517,rs6809699),P2Y1(rs1371097,rs12497578,rs1439010)18 kinds of SNP had no significant difference between the two groups(P > 0.05).4 During 6-months' follow up,a total of 5(14.29%)cases adverse events occured.There were 3(8.57%)casesprimary endpoint events,including 1 in the AS group and 2 in the AR group;and 2(5.71%)cases secondary endpoint events,including 1(2.86%)case of cerebral hemorrhage,and 1(2.86%)case of death.There was no significant difference in the recurrence rate of ischemic stroke(12.5% vs 5.3%,P=0.604)between the AS group and the AR group.5 Statistical analysis of mRS at 1 month,3 months and 6 months in AS group and AR group showed that there was no significant difference between the two groups.6 SNP genotypes COX-1(rs1330344),GPIa/IIa(rs1126643,rs1062535),GP?(rs1613662,rs1671153,rs12610286),GP?b(rs6065),TXA2(rs1131882,rs2238634,rs4523,rs4806942),P2Y12(rs10935838,rs2046934,rs5853517,rs6809699),P2Y1(rs1371097,rs12497578,rs1439010)had no relationship with mRS score at 90 days.Conclusion1 In present study,the incidence of AR in patients with recurrent ischemic stroke was45.71%.2 Smoking is a risk factor for aspirin resistance.The risk of aspirin resistance in smokers with ischemic stroke is 0.204 times higher than no-smokers.3 19 gene polymorphisms of COX-1(rs1330344),GP?b/?a(rs5918),GPIa/IIa(rs1126643,rs1062535),GP?(rs1613662,rs1671153,rs12610286),GP?b(rs6065),TXA2(rs1131882,rs2238634,rs4523,rs4806942),P2Y12(rs10935838,rs2046934,rs5853517,rs6809699),P2Y1(rs1371097,rs12497578,rs1439010)were not associated with aspirin resistance.4 There was no significant relationship between genotype and 90-day mRS score.5 There was no significant difference in stroke recurrence between AR group and AS group during the 6-month follow-up period.