Abstract 12886: Rare Variants in GJA5 Associated with Early-Onset Atrial Fibrillation
Background: GJA5 encodes the atrial-specific gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. Gollob et al. were the first to associate mutations in this gene with atrial fibrillation (AF) in a study published in NEJM in 2006. They also showed that genetic variants in GJA5 can lead to altered expression of the gene-product Cx40, and changes in the functional coupling of wild type Cx43. The regulatory single nucleotide polymorphism (SNP) rs10465885 in GJA5 was recently associated with early-onset lone AF (<60 y) and with the levels of Cx40 mRNA. We hypothesized that this gene would have strong impact in patients with onset of lone AF before the age of 50, and that the findings regarding rs10465885 could be replicated in this group.
Methods: The coding region and flanking intron sequences of GJA5 was resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9, 82% men, median age 44 y, IQR 38-48 y) and in 216 controls (52% men, median age 39 y, IQR 30-48 y). The SNP rs10465885 was genotyped in 342 patients and 534 controls (52% men, median age 65 y, IQR 60-70 y) and ORs were calculated for different genetic models.
Results: Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A-allele compared to controls (OR=0.77, p=0.011). When resequencing GJA5, we identified the mutation A96S, which previously has been associated with lone AF. This was not present in our controls and has not been described in any publicly available database or in the NHLBI Exome Variant Server, holding data on 10.758 alleles.
Conclusions: To our knowledge, this is the largest reported cohort of patients with such a highly selected AF phenotype, and no other study has investigated the impact of both rare and common variants in GJA5 in these patients. We report a significant association of the A-allele of the promoter variant rs10465885 in GJA5, with early-onset lone AF. The biological link between this variant and the development of AF might be that increased levels of the atrial-specific gap-junction protein Cx40, could lead to disturbance of the natural connexin balance, resulting in decreased atrial conduction velocity and thus an increased risk of AF.
- © 2012 by American Heart Association, Inc.