Correlation Evaluation Of Common Single Nucleotide Polymorphisms In NOS1AP Gene And Sudden Cardiac Death

Background: Sudden death means unexpected death that is instantaneous or occurs within minutes from any cause other than violence.The vast majority of sudden death is cardiogenic,which is called sudden cardiac death(SCD).SCD has become the main cause of cardiovascular death due to its suddenness and difficulty in prevention.The direct cause of SCD is often rapid malignant ventricular arrhythmia.The etiology of SCD varies in different age groups,and genetic factors are important in the course of the disease.Finding the pathogenic gene of SCD has a certain guiding role in clinical practice.NOS1AP(nitric oxide synthase 1 adaptor protein)gene,a non-ionic channel gene related to SCD and ventricular arrhythmia,has become a “hot” gene in recent years.Moreover,NOS1 AP is also associated with the QT interval.However,most of the current studies are based on foreign populations,and there are few relevant data for Chinese people.In addition,there are still some inconsistent conclusions about the correlation between NOS1 AP SNP and sudden death and QTc interval.Screening for SNPs of NOS1 AP gene that have been widely studied and verified in clinical work is conducive to the discovery of truly clinically meaningful SNPs.According to the above,this study systematically evaluated the relationship and clinical value between SNPs related to sudden death in NOS1 AP and sudden death through detailed metaanalysis and clinical research.The idea of the research also explores a new avenue for evaluating the clinical value of SNP.The thesis includes three parts.Part I: Conduct a preliminary evaluation of SNPs that have been extensively studied in NOS1 AP through a meta-analysis of the relationship between SNPs and sudden death.Part II: Conduct a meta-analysis to evaluate the relationship between significant SNPs and QT interval to explore the possible mechanism through which these SNPs act on SCD.Part III: Perform an association study of SNPs in NOS1 AP and patients with implantable cardioverter defibrillator(ICD)for secondary prevention.The significant SNPs were identified by comparison between ICD secondary prevention patients and healthy people,as well as the correlation study between SNPs and QTc interval.The patients were followed up at the same time of enrollment to further analyze the specific correlation between SNP and ICD secondary prevention,and to evaluate the relationship between SNP genotype and mortality.NOS1 AP SNPs related to sudden death were systematically evaluated for the first time through three parts of research.An approach of exploring SNP value by meta-analysis combined with clinical research was formed to support potential clinical applications of SNP.Part I: Meta-analysis of the relationship between NOS1 AP SNPs and sudden deathObjective: Verify the relevance of common SNPs in NOS1 AP and sudden death by metaanalysis.Methods: Search for relevant literature in Pub Med,EMBASE,Science Direct,Google Scholar,Wanfang and CNKI databases with a deadline of December 2019.Screen SNPs in NOS1 AP gene related to sudden death to identify the extensively studied SNPs from these articles.Analyze the pooled OR and HR of sudden death for these SNPs in four gene models(allele model,dominant model,recessive model,homozygous model)then.Results: The most frequent four SNPs were rs12143842(C>T),rs10494366(G>T),rs16847548(T>C)and rs12567209(G>A),accounting for 49% of the total number.It is insufficient to reach a conclusion that rs10494366 associated with sudden death with the heterogeneous pooled effect.There were 7 cohort studies referring to the relationship between rs10494366 and sudden death.After meta-analysis,the pooled HR was 1.313(Z=3.01,P=0.003).These studies were all conducted in Caucasians with different diseases.The conclusion on the other three locus needs to be further confirmed as heterogeneous results.Conclusion: The cohort studies focus on rs10494366 and sudden death displayed well credibility with the potential virtual conclusion that rs10494366 increased the risk of sudden death.Part II:Meta-analysis of the association between rs10494366 and QT intervalObjective: Contemporary researches identified rs10494366 in NOS1 AP gene as a new genetic marker in modulating QT interval in general populations.However,the conclusions are not exactly coincident.We conducted a system evaluation of the relation of rs10494366 and QT interval.Methods: Search for articles from Pub Med,Embase,Science Direct,Pub Med,Embase, Science Direct,Google Scholar,Wan Fang and CNKI database with a deadline of December 2019.Meta-analysis of the association between rs10494366 and QTc interval was performed using STATA after strictly screening literature.Results: Among the 18 studies,8 cohorts showed the correlation between rs10494366 and QTc interval.The pooled effect size was 2.41 for the correlation but with huge statistics heterogeneity(Q=86.23,I2=80.3%).Furthermore,when stratified by gender,subject number,age,diseases,study design and ethnicity,we observed significant effect of rs10494366 on QT interval in women,as well as in diabetes patients and African.,Whereas,the pooled effect size was not significant in Asian.Conclusion: As revealed by our meta-analysis,rs10494366 correlate with QTc interval in female,diabetes patients and African.Part III: Evaluating Common NOS1 AP Variants in Patients with Implantable Cardioverter Defibrillator for Secondary PreventionObjective: ICD can identify rapid ventricular arrhythmias and treat them to prevent SCD.This study aims to explore the clinical utility and implications of SNPs in NOS1 AP in patients with ICD for secondary prevention.Methods: We firstly conducted a case-control study to evaluate the associations between SNPs in NOS1AP(rs12143842,rs10494366,rs12567209 and rs16847548)and patients with ICD for secondary prevention.The relevant of QTc interval with SNPs were also evaluated at the same time.Then the clinical values of the significant SNPs were further investigated in these patients.All patients were divided into three groups according to different genotypes of the significant SNPs.ICD interrogation data at 3,12 months,and 3 years after implantation,which include rapid ventricular arrhythmia episodes and appropriate therapies,were analyzed in three genotypes.Results: Rs12143842 and rs10494366 were correlated with QTc interval.Case-control study revealed significant allelic association between rs10494366 and ICD recipients who experienced appropriate therapies.After a mean follow-up of 31.70 ± 9.15 months,it was found that there were differences in ICD discharge frequency and distribution among the three genotypes of rs10494366,and there was a positive correlation between TT genotype and ICD discharge.Furthermore,Kaplan-meier curve and Cox regression analysis showed that rs10494366 TT genotype was a high risk factor for SCD,and the risk of death increased by 2.944 times compared with GG genotype.Conclusion: This study found that rs10494366 TT genotype in NOS1 AP gene increased discharge treatment events in patients with ICD secondary prevention,which can be used as a risk predictor for such patients.