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A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation.

ABSTRACT: BACKGROUND:A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown. METHODS AND RESULTS:Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, -44G?A) was not associated with Cx40 mRNA levels. However, a common SNP (rs10465885) located in the TATA box of an alternative Cx40 promoter was strongly associated with Cx40 mRNA expression (P<0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in cultured murine cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (P<0.0001). Both rs35594137 and rs10465885 were tested for association with early-onset lone AF (?60 years of age) in 384 cases and 3010 population control subjects. rs10465885 was associated with the AF phenotype (odds ratio, 1.18; P=0.046). This result was confirmed in a meta-analysis including 2 additional early-onset lone AF case-control cohorts (odds ratio, 1.16, P=0.022). rs35594137 was not associated with the lone AF phenotype in any of the cohorts studied or in a combined analysis. CONCLUSIONS:A previously described Cx40 promoter SNP was not found to influence Cx40 expression or risk of AF. We describe an alternate promoter polymorphism that directly affects levels of Cx40 mRNA in vivo and is associated with early-onset lone AF.

SUBMITTER: Wirka RC

PROVIDER: S-EPMC3057452 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation.

Wirka Robert C RC Gore Shamone S Van Wagoner David R DR Arking Dan E DE Lubitz Steven A SA Lunetta Kathryn L KL Benjamin Emelia J EJ Alonso Alvaro A Ellinor Patrick T PT Barnard John J Chung Mina K MK Smith Jonathan D JD

Circulation. Arrhythmia and electrophysiology 20101113 1

<h4>Background</h4>A common single-nucleotide polymorphism (SNP) in the promoter of the Connexin-40 (Cx40) gene GJA5 was suggested to affect Cx40 promoter activity and the risk of atrial fibrillation (AF), but the role of other common Cx40 polymorphisms is unknown.<h4>Methods and results</h4>Eight SNPs within the Cx40 gene region were tested for association with Cx40 levels measured in atrial tissue from 61 individuals. The previously described Cx40 promoter SNP (rs35594137, -44G→A) was not asso ...[more]

PMID: 21076161

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Project description:The atrial gap junction protein connexin-40 (Cx40) has been implicated to play an important role in atrial conduction and development of atrial fibrillation (AF). However, the frequency of Cx40 mutations in AF populations and their impact on Cx40 expression remains unclear. In this study, we sought to identify polymorphisms in the Cx40 gene GJA5, investigate the potential functional role of these polymorphisms, and determine their allelic frequencies. The prevalence of nonsynonymous Cx40 mutations in blood and atrial tissue was also compared to mutation frequencies reported in prior studies.We conducted direct sequencing of the GJA5 coding and 3' UTR regions in blood samples from 91 lone AF subjects and 67 atrial tissue-derived samples from a lone cohort, a mixed AF cohort, and several transplant donors. Reporter gene transfection and tissue allelic expression imbalance assays were used to assess the effects of a common insertion/deletion polymorphism on Cx40 mRNA stability and expression.We identified one novel synonymous SNP in blood-derived DNA from a lone AF subject. In atrial tissue-derived DNA from lone and mixed AF subjects, we observed one novel nonsynonymous SNP, one rare previously reported synonymous SNP, and one novel 3' UTR SNP. A previously noted 25 bp insertion/deletion polymorphism in the 3' UTR was found to be common (minor allele frequency = 0.45) but had no effect on Cx40 mRNA stability and expression. The observed prevalence of nonsynonymous Cx40 mutations in atrial tissues derived from lone AF subjects differed significantly (p = 0.03) from a prior atrial tissue study reporting a high mutation frequency in a group of highly selected young lone AF subjects.Our results suggest that Cx40 coding SNPs are uncommon in AF populations, although rare mutations in this gene may certainly lead to AF pathogenesis. Furthermore, a common insertion/deletion polymorphism in the Cx40 3' UTR does not appear to play a role in modulating Cx40 mRNA levels.

Dataset Information

A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation.

Publications

A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation.

Similar Datasets

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