Association of Human Connexin40 Gene Polymorphisms With Atrial Vulnerability as a Risk Factor for Idiopathic Atrial Fibrillation

Abstract

Abstract-Alterations in distribution, density, and properties of cardiac gap junctions, which mediate electrical coupling of cardiomyocytes, are considered potentially arrhythmogenic. We recently reported 2 linked polymorphisms within regulatory regions of the gene for the atrial gap junction protein connexin40 (Cx40) at nucleotides Ϫ44 (G3 A) and ϩ71 (A3 G), which were associated with familial atrial standstill. The present study examined whether these Cx40 polymorphisms were associated with increased atrial vulnerability in vivo and arrhythmia susceptibility. In 30 subjects without structural heart disease, of whom 14 had documented sporadic paroxysmal atrial fibrillation (AF) and 16 had no AF history, inducibility of AF was assessed using an increasingly aggressive atrial stimulation protocol. Coefficient of spatial dispersion of refractoriness (CD) was calculated. CD was defined as the SD of 12 local mean fibrillatory intervals recorded at right atrial sites, expressed as a percentage of the overall mean fibrillatory interval. Cx40 genotypes were determined by direct DNA sequencing. Subjects were stratified according to normal or increased CD with a cutoff value of 3.0, because CD Ͼ3.0 was previously shown to be strongly associated with enhanced atrial vulnerability. The prevalence of the minor Cx40 allele (Ϫ44A) and Ϫ44AA genotype was significantly higher in subjects with increased dispersion (nϭ13) compared with those with CD Յ3.0 (nϭ17; Pϭ0.00046 and Pϭ0.025; odds ratios of 6.7 and 7.4) and a control population (nϭ253; Pϭ0.00002 and Pϭ3.90ϫ10 Ϫ7). Carriers of Ϫ44AA genotype had a significantly higher CD compared with those with Ϫ44GG genotype (6.37Ϯ1.21 versus 2.38Ϯ0.39, Pϭ0.018), whereas heterozygotes had intermediate values (3.95Ϯ1.38, NS). All subjects with increased CD had a history of idiopathic AF compared with only 1 subject with normal CD. The Ϫ44A allele and Ϫ44AA genotype were significantly more frequent in subjects with prior AF than in those without (Pϭ0.0019 and Pϭ0.031; odds ratios 5.3 and 6.2). This study provides strong evidence linking Cx40 polymorphisms to enhanced atrial vulnerability and increased risk of AF. The full text of this article is available online at http://circres.ahajournals.org. (Circ Res. 2004;95:e29-e33.)

Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms

“…In the Dutch AS pedigree, affected individuals exclusively carry both the SCN5A mutation (D1275N) and homozygous SNPs in the regulatory region of Cx40 which reduces Cx40 expression in vitro 6 . Furthermore, these CX40 SNPs have been clinically associated with enhanced atrial vulnerability and increased risk of atrial fibrillation 7 . The prevalence of Cx40 SNPs in the general population is not rare and the Cx40 promoter activity of homozygous SNP is less than 50% of WT 6 , suggesting that the heterozygous Cx40 gives rise to intermediate promoter activity, and the clinical manifestation of Cx40 SNPs alone may not be apparent.…”

“…Cx40 is a gap junction protein predominantly expressed in the atrium and the specialized conduction system, and the single nucleotide polymorphisms (SNPs) result in reduced Cx40 expression in vitro 6 . Furthermore, these SNPs have been clinically associated with enhanced atrial vulnerability and increased risk of atrial fibrillation 7 . These results suggest that the D1275N allele alone may not be sufficient to manifest a severe clinical phenotype in AS, and the Cx40 SNPs may cause a genetic predisposition which in turn disrupts the spatial distribution of Cx40 influencing atrial conduction and excitability.…”

Ischemic, genetic and pharmacological origins of cardiac arrhythmias: The contribution of the Quebec Heart Institute

“…We initially performed a sequence analysis of Cx40, an isoform specifically expressed in human atria, in two French-Canadian families presenting the familial form of AF, but we found no correlation with the disease (91). However, other case-control association studies (92) in patients with structural heart disease and AF have suggested a predisposition to AF for patients with a Cx40 gene polymorphism. We also searched for mutations in hK v 1.5, a major repolarizing current of the human atria.…”

A pilot study to estimate the feasibility of assessing the relationships between polymorphisms in hKv1.5 and atrial fibrillation in patients following coronary artery bypass graft surgery

“…As pointed out by Roberts (25), although seven chromosomal loci mapped and four genes identified so far have been found in families with lone AF, the small size of investigated families has precluded identification of genes by conventional genetic linkage analysis. Other case-control association studies in patients with structural heart disease and AF suggested a predisposition to AF in patients with a polymorphism in the angiotensin-converting enzyme gene (26) or the connexin-40 gene (27). However, the number of patients in these studies was insufficient, and additional analyses are needed before making a conclusion.…”