title: Promoter polymorphism G-6A, which modulates angiotensinogen gene expression, is associated with non-familial sick sinus syndrome.
abstract: BACKGROUND
  It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS.
  
  
  METHODS
  In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA).
  
  
  RESULTS
  Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58-5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54-4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01).
  
  
  CONCLUSIONS
  G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jan-Yow
authors.initials: JY
authors.lastname: Chen
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Liou
authors.forename: Hong-Dar Isaac
authors.initials: HD
authors.lastname: Wu
authors.forename: Kuo-Hung
authors.initials: KH
authors.lastname: Lin
authors.forename: Kuan-Cheng
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000368:Aged; D000808:Angiotensinogen / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006339:Heart Rate / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012804:Sick Sinus Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D014158:Transcription, Genetic; D014463:Ultrasonography
chemical_list: C534931:AGT protein, human; D000808:Angiotensinogen