Promoter Polymorphism G-6A, which Modulates Angiotensinogen Gene Expression, Is Associated with Non-Familial Sick Sinus SyndromeReportar como inadecuado




Promoter Polymorphism G-6A, which Modulates Angiotensinogen Gene Expression, Is Associated with Non-Familial Sick Sinus Syndrome - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Jan-Yow Chen, Ying-Ming Liou , Hong-Dar Isaac Wu, Kuo-Hung Lin, Kuan-Cheng Chang

Fuente: http://plos.srce.hr/



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