RGD Reference Report - Promoter polymorphism G-6A, which modulates angiotensinogen gene expression, is associated with non-familial sick sinus syndrome. - Rat Genome Database

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Promoter polymorphism G-6A, which modulates angiotensinogen gene expression, is associated with non-familial sick sinus syndrome.

Authors: Chen, JY  Liou, YM  Wu, HD  Lin, KH  Chang, KC 
Citation: Chen JY, etal., PLoS One. 2012;7(1):e29951. doi: 10.1371/journal.pone.0029951. Epub 2012 Jan 5.
RGD ID: 8548870
Pubmed: (View Article at PubMed) PMID:22242192
DOI: Full-text: DOI:10.1371/journal.pone.0029951

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). CONCLUSION: G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility.

Annotation

Disease Annotations    
sick sinus syndrome  (IAGP,ISO)

Phenotype Annotations    

Human Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Agt  (angiotensinogen)

Genes (Mus musculus)
Agt  (angiotensinogen (serpin peptidase inhibitor, clade A, member 8))

Genes (Homo sapiens)
AGT  (angiotensinogen)


Additional Information