title: Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.
abstract: BACKGROUND
  Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group.
  
  
  METHODS
  The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios 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 with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles).
  
  
  CONCLUSIONS
  We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Christophersen
authors.forename: Haya N
authors.initials: HN
authors.lastname: Holmegard
authors.forename: Javad
authors.initials: J
authors.lastname: Jabbari
authors.forename: Ahmad
authors.initials: A
authors.lastname: Sajadieh
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.forename: Arnljot
authors.initials: A
authors.lastname: Tveit
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016001:Confidence Intervals; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006325:Heart Atria / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D012333:RNA, Messenger; D000097003:Gap Junction alpha-5 Protein