The association of human connexin 40 genetic polymorphisms with atrial fibrillation

Background: There is evidence showing that genetic factors contribute to the pathogenesis of atrial fibrillation (Af). We investigated the association between Af and polymorphisms of the connexin 40 (Cx40) gene, which is important in the electrical coupling between atrial myocytes. Methods: We performed an association study between two Cx40 single nucleotide polymorphisms (SNPs) (Cx40 - 44 and + 71 allele) and Af. We enrolled 173 patients with Af, and the control group consisted of 232 patients without Af. The luciferase assay was performed to evaluate the promoter activities of different Cx40 haplotypes in cultured atrial myocytes. Results: We found that the two SNPs were both significantly associated with Af. In pairwise linkage disequilibrium analysis, the two SNPs were completely linked (Cx40 - 44G always associated with Cx40 + 71A; Cx40 - 44A associated with Cx40 + 71G, P < 0.001). In haplotype analysis, we demonstrated that the frequency of Cx40 (- 44A,+ 71G) was significantly higher in the Af group than that in the control group (P < 0.006, odds ratio = 1.514, 95% confidence interval 1.13-2.04). We also performed genotype analysis using several genetic models, finding that the recessive model showed the lowest P value (P < 0.004) and the largest odds ratio (2.53, 95% confidence interval 1.23-5.19). In promoter activity studies using luciferase as the reporter, Cx40 (- 44A,+ 71G) had significantly lower promoter activity than that of the Cx40 (- 44G,+ 71A) in atrial myocytes. Conclusions: The two SNPs in the promoter region of the Cx40 gene were significantly associated with Af. The Cx40 (- 44A + 71G) haplotype was associated with a higher risk for Af. This haplotype also had significantly lower promoter activity in atrial myocytes.