The Association Between NLRP3 Gene Polymorphism With Susceptibility For Large Artery Atherosclerotic Ischemic Stroke And Microembolic Signals

Purpose: With the development of our society and aging of the population,the incidence of stroke has increased,which is the main cause of death and disability.Ischemic stroke(IS)accounts for 65%-80% of new increased stroke cases.According to the TOAST system,Large artery atherosclerosis(LAA)ischemic stroke(IS)is the most common IS subtype,which is mainly caused by atherosclerosis.Nucleotide-binding domain-like receptor protein 3(NLRP3)plays a crucial role in the pathogenesis of atherosclerosis.In patients with large artery occlusive disease,active microemboli are released from the unstable atherosclerotic lesions and lead to acute cerebral infraction.And microemboli are clinically important for indicating an increased risk of IS.The aim of this study is to investigate the relationship between NLRP3 gene polymorphisms and susceptibility for LAA IS and microembolic signals(MES)in the Chinese Han population.Methods: We studied 293 patients diagnosed with LAA IS and 265 controls.Transcranial Doppler(TCD)was used to monitor the MES in all of the patients within 72 h of admission.Depending on the presence or absence of MES,the patients were divided into MES-positive and MES-negative subgroups.Questionnaire surveys were conducted to investigate the general status of the subjects.Genomic DNA was extracted from peripheral blood leukocytes using the DNA kit.PCR-RFLP or direct sequencing were used to analyze three NLRP3 gene polymorphisms:rs4612666、rs10754558、rs7512998.Statistical analyses were performed using SPSS 20.0.Results: Seventy-six patients presented with MES and the MES-positive rate was 25.94%.Logistic regression analysis showed that the TT genotype frequency for the rs4612666 gene polymorphism was higher in study patients than in the controls(adjusted P=0.001)and higher in MES-positive patients compared to MES-negative patients(adjusted P=0.015).The T allele of rs4612666 was associated with an increased risk for developing LAA IS and MES(P=0.001;P=0.015 respectively).Prevalence of the CCC haplotype was higher in the controls than in the patients(P=0.009)and prevalence of the TGT haplotype was lower in the controls than in the patients(P=0.019).A P value of less than 0.05 was considered to be statistically significant.Conclusions: The NLRP3 rs4612666 gene polymorphism may be related to theoccurrence of LAA IS,the TT genotype and T allele may be associated with a susceptibility for LAA IS.The CCC haplotype may play a protective role against LAA stroke,while the TGT haplotype may have the opposite effect.The TT genotype and T allele may rise the occurrence of MES,suggesting that the NLRP3 gene polymorphism increases the susceptibility of LAA IS by changing the plaque vulnerability.