Association Between Single Nucleotide Polymorphisms Of SCN5A Gene And Sick Sinus Syndrome

Background:The human cardiac sodium channel(SCN5A) is responsible for the fast depolarization upstroke of the cardiac action potential and serves as a molecular target for anti-arrhythmic drugs.Mutations in the human cardiac sodium channel gene have been previously discovered in a spectrum of cardiac rhythm disorders:The long QT internal syndrome,Brugada syndrome,idiopathic ventricular fibrillation, conduction system disease and sick sinus syndrome.An H558R polymorphism in SCN5A gene was shown to relate with Brugada syndrome.An S1102Y polymorphism in SCN5A,with a minor allele frequency of 7%in African Americans, was subsequently shown to increase the risk of ventricular arrhythmias by eightfold. More recently,loss-of-function mutations in SCN5A have been linked to a syndrome of dilated cardio-sympathy(DCM) and AF.Gain-of-function mutations in SCN5A cause the long QT syndrome,whereas the other conditions are caused by mutations that reduce sodium channel current.Gouas found that H558R polymorphism and D1819D polymorphism related to QT c interval length prominencly.LQT3 carriers regularly present with bradycardia and sinus pauses.Therefore,Veldkamp MW studied the effect of 1795insD Na+ channel mutation on sinoatrial pacermaking.The 1795insD channel was previously characterized by the presence of a persistent inward current at -20mVand a negative shift in voltage dependence of inactivation.Thus, Na+ channel mutation displaying an Ipst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients,whereas SA node pauses or arrest may result from failure of SA node cells to depolarize under conditions of extra net inward current.The findings provide a rationale to test SCN5A as a candidate gene for sick sinus syndrome.Sick sinus syndrome(SSS) is usually a disease of the elderly produced by idiopathic degeneration of the senatorial node.Its initial manifestations range from asymptomatic to nonspecific and include palpitations,fatigue,confusion,and even syncope and sudden death.Electrocardiography evidence of SSS includes inappropriate sinus bradycardia,sinus pause or arrest,or sinus exit block.These brady arrhythmias may alternate with tachyarrhythmia,especially artial fibrillation,to create the tachycardia-bradycardia syndrome.The diagnosis of SSS may be established by electrocardiography or ambulatory monitoring in the majority of cases. Medications such as dioxin,beta-blockers,and calcium blockers may initiate or worsen the manifestations of SSS.Permanent pacing is indicated for symptomatic brad-arrhythmias.Progression of SSS is mostly dependent on the presence and severity of associated coronary or hypertensive heart disease.Our research is to investigate the possible association between polymorphisms of SCN5A gene and sick sinus syndrome in Han population of South China.These also benefit to provide the theoretical basis for the treatment and lay preliminary basis for the future of gene therapy and gene diagnosis.ObjectivesTo investigate the possible association between polymorphisms of SCN5A gene and sick sinus syndrome in Han population of South China.MethodsA case-control design was applied in this study.A total of One hundred and eight unrelated hospitalized patients suffered from SSS were enrolled from Na-fang Hospital between October 2006 and December 2007.One hundred and twenty-three control subjects were recruited from individuals participating in a community-based survey in guang-zhou district.The genomic DNA was extracted from blood,One SNP s of SCN5A gene D1819D was genotyped by restriction fragment length polymorphism(RFLP) in all subjects.All data are presented as mean value±standard of the mean.The significance of differences between groups was assessed using Chi-square test.Unvaried analysis was applied to measure the association of single polymorphism with SSS.binary logistic regression was performed to investigate the independent effect between the gene type of the polymorphisms and SSS.Statistically significant difference was defined as P＜0.05.All analyses were performed using the SPSS 13.0 statistical software.ResultsAge distinction was compared between SSS subjects and normal control, t=0.814,P＞0.05.Sexual distinction was compared between SSS subjects and normal control,P=0.246(P＞0.05).The frequencies of genotype of CC,CT and TT were respectively 24,48,36 in SSS subjects.The frequencies of genotype of CC,CTandTT were respectively 48,45and30 in normal control.There was a significant difference in the distributions of the gene-types(CC,CT,TT) between SSS subjects and normal control(χ2=7.701,P=0.021)Also significant difference was observed in D1819D allele frequency between the two groups(χ2 =7.628,P=0.006).In Han population of South China minor allele frequencies of D 1819D was 0.427.The presence of C allele of D 1819D gene was found to be a greater protective factor in normal control than in SSS subjects.The odds radio(OR) of CC was 0.417(0.209-0.830),when compared with TT genotype,the P=0.03(P＜0.05).ConclusionsThe study suggested existence of D1819D polymorphisms of SCN5A gene might be related to SSS in Han Nationality of Southern China.The C allele may be protective,while the T allele may be susceptibility gene for SSS.