Relationship Between Single Nucleotide Polymorphism Of Interleukin-17 Receptor C Rs376511 And Ischemic Stroke

Stroke has become the leading cause of disability and death among adults in China.Research and clinical practice have found that inflammation is closely related to the occurrence and development of ischemic stroke.Ischemic stroke approximately accounted for 80%of all stroke.Interleukin-17 receptor C(IL-17 RC)is a newly discovered IL-17 family receptor and has a wide distribution in tissues,and can specifically bind to IL-17.IL-17 is a confirmed risk factor of ischemic stroke,which has the physiological function of promoting the formation of intracranial atherosclerotic plaque.IL-17 can bind to its receptor IL-17 RC.Then IL-17 can stimulate the secretion and release of IL-6,IL-8,IL-1βand TNF-α and promote the accumulation of neutrophils,which lead to ischemic stroke from many aspects.Studies show that IL-6 can lead to the formation of atherosclerotic plaque and induce the rupture of atherosclerotic plaque,causing the occurrence of acute ischemic stroke.IL-8 has chemotactic effect on various inflammatory cells and promotes local inflammatory response.Studies have shown that IL-1β can promote leukocyte adhesion to vascular endothelial cells and cause leukocyte aggregation in ischemic areas and aggravate inflammatory response,which can directly induce neuronal apoptosis and inhibit the role of anticoagulant proteins.Studies have shown that anti-IL-1β can significantly reduce the severity of cerebral edema after cerebral ischemia,and significantly reduce the size of infarction.TNF-α is another very important inflammatory cytokine in the development of ischemic brain injury.TNF-αis another important inflammatory cytokine in the development of ischemic brain injury,which can contract blood vessels and inhibit the activity of anticoagulants.In summary,IL-17 is a definite risk factor of ischemic stroke,and its mechanism may be associated with stimulating the secretion and release of IL-6,IL-8,IL-1β and TNF-α,etc.The physiological role of IL-17 needs to be achieved by binding to receptor.According to a recent study,the single nucleotide polymorphism(SNP)of IL-17 RC gene(rs376511)is associated with susceptibility to Thromboangiitis Obliterans(TAO)in Xinjiang,and IL-17 RC may be involved in the development of TAO.Accordingly,we speculate that IL-17 RC may be related to the occurrence and development process of ischemic stroke,and that the single-nucleotide polymorphism at IL-17 RC rs376511 may be related to the susceptibility to ischemic stroke.Its action mechanism may be that the Single nucleotide polypeptide(SNP)affects the expression level of IL-17 RC,and thus affects the role of IL-17.IL-17 is a risk factor for the development of ischemic stroke.Different rs376511 genotype can cause differences in the expression content of IL-17RC,and downregulated IL-17 RC can reduce the effect of IL-17 in stimulating the secretion release of IL-1,IL-6,IL-8 and TNF-α.Upregulated IL-17RC leads to the increased effects of IL-17 in stimulating IL-1,IL-6,IL-8 and TNF-α.Thus,it has different effects on the development and prognosis of ischemic stroke.Part Ⅰ:Relationship between the single nucleotide polymorphism of IL-17 RC rs376511 and ischemic strokeObjectiveTo investigate the relationship between single nucleotide polymorphism of interleukin-17 receptor C gene rs376511 and ischemic stroke and its mechanism.Then the pathogenesis of ischemic cerebrovascular disease was studied.MethodsA total of 300 patients with the first ischemic stroke were selected as the case group and 300 people were selected from the physical examination of the same hospital as the control group according to the sex and age of the patients.The genotypes of IL-17 RC rs376511 were detected by PCR-RFLP,and the expression levels of IL-17,IL-17 RC,IL-6,IL-8,IL-1β and TNF-α genes were detected by RT-qPCR,and IL-17 and IL-17 RC protein were detected by Western Blot.Univariate analysis was performed with independent group t test,ANOVA or chi-square test,and multivariate analysis was performed with binary logistic regression model.The predictive values of related inflammatory cytokines were evaluated with the area under the Receiver Operating Characteristic Curve(AUC).Finally,the diagnostic indexes were calculated.Results1.After adjustment for BMI,hypertension,smoking,alcohol consumption,diabetes,atrial fibrillation and hyperlipidemia,rs376511 AA[the odds ratio(OR):2.185,95%confidence Interval(CI):1.376-4.232]and AG(OR:1.683,95%CI:1.114-2.671)genotypes were independent risk factors for ischemic stroke.2.The expression levels of IL-17,IL-17 RC,IL-6,IL-8,IL-1β and TNF-α mRNA showed the tendency of AA genotype>AG genotype>GG genotype.In addition,the expression levels of IL-17 and IL-17 RC protein also showed the tendency of AA genotype>AG genotype>GG genotype.3.After adjustment for possible confounding factors,high expression of IL-17 RC,IL-6,IL-8,IL-1β and TNF-α were independent risk factors for ischemic stroke.The expression level of IL-17 RC mRNA>Q2(1.81),IL-6 mRNA>Q2(2.16),IL-8 mRNA>Q2(1.50),IL-1β mRNA>Q2(3.49),and TNF-α mRNA>Q2(2.45)had ORs of 3.498,3.287,2.589,3.195 and 2.632,respectively.4.When the expression levels of IL-17 RC,IL-6,IL-8,IL-1β and TNF-α mRNA were used to predict ischemic stroke individually,the AUC of IL-17 RC mRNA was more than 0.800,but the AUCs were all less than 0.800 for all other inflammatory cytokines.5.When the expression levels of IL-17 RC,IL-6,IL-8,IL-1β and TNF-α mRNA were used to predict ischemic stroke jointly.The AUCs were significantly increased with the maximum of 0.865 for the combination of IL-17 RC,IL-6 and IL-1β.In addition,the value of prediction may not be improved by adding the indexes of joint prediction.Conclusions1.The SNP of IL-17RC rs376511 was associated with ischemic stroke,and AA and AG genotypes were independent risk factors for ischemic stroke.The mechanism might be associated with the increase of the expression of IL-17 RC in AA genotype and AG genotype.The combination of IL-17 with elevated IL-17 RC resulted in the increase of the secretion of IL-6,IL-8,IL-1β and TNF-α,and finally leaded to the occurrence of ischemic stroke.2.After adjustment for BMI,hypertension,smoking,drinking,diabetes,atrial fibrillation and hyperlipidemia,the expression levels of IL-17 RC,IL-6,IL-8,IL-1βand TNF-α were risk factors of ischemic stroke.3.The expression level of IL-17 RC had a high value in predicting ischemic stroke,while the expression levels of IL-6,IL-8,IL-1β and TNF-α had medium values in predicting ischemic stroke.4.The parallel prediction of IL-17 RC,IL-6,IL-8,IL-1β and TNF-α had significant values compared with individual prediction,and parallel prediction of IL-17 RC,IL-6 and IL-1β had the highest predictive value with a AUC of 0.865.In addition,the predictive value may not be improved by adding the indexes of parallel prediction.In practice,parallel prediction of IL-17 RC combined with one or two of IL-6,IL-8,IL-1β or TNF-α was enough.Part Ⅱ:Relationship between the single nucleotide polymorphism of IL-17 RC rs376511 and prognosis of ischemic strokeObjectiveTo explore the relationship between single nucleotide polymorphism of interleukin-17 receptor C gene rs376511 and the prognosis of ischemic stroke patients,and to judge the prognosis of patients from the gene level.MethodsA total of 300 patients with ischemic stroke were enrolled in this study.All patients were treated with conventional stroke.The treatment plan was made according to the early diagnosis and treatment guidelines.The genotypes of IL-17 RC rs376511 were detected by PCR-RFLP,and the therapeutic effect,recurrence and survival were followed up.Chi-square test was used to compare the therapeutic effect,recurrence and death of different genotypes.Binary logistic regression model was used to analyze the relationship between different genotypes and therapeutic effect and recurrence.Results1.The mRS score was used.The ratio of different genotype of ischemic stroke patients with good therapeutic effect was GG genotype>AG genotype>AA genotype(77.61%vs 68.14%vs 59.17%),the mortality rate was GG genotype<AG genotype<AA genotype(1.49%vs 4.42%vs 10.00%);recurrence rate was GG genotype<AG genotype<AA genotype(10.45%vs 16.81%vs 27.50%).2.After adjusting for age,sex,stroke etiology,stroke severity and treatment with binomial logistic regression model,AG genotype(OR:1.974,95%CI:1.207-2.746,P<0.05)and AA genotype(OR:2.357,95%CI:1.316-4.074,P<0.05)were independent risk factors for poor treatment outcome,and AG genotype(OR:1.813,95%CI:1.168-2.609,P<0.05)and AA genotype(OR:2.126,95%CI:1.219-3.807,P<0.05)were independent risk factors for recurrence.ConclusionsIL-17 RC rs376511 AG genotype and AA genotype were independent risk factors for poor therapeutic effect of ischemic cerebrovascular disease,and AG genotype and AA genotype were independent risk factors for recurrence of ischemic cerebrovascular disease.