title: Cx40 polymorphism in human atrial fibrillation.
abstract: Previous studies have shown that two linked polymorphisms within regulatory regions of the gene for connexin40 (Cx40), at nucleotides -44 (G --> A) and +71 (A --> G) occur in about 7% of the general population. Cx40 is abundant in the atrium, and homozygosity for the linked polymorphisms combined with an SCN5A mutation appeared to be responsible for familial atrial standstill. We hypothesized that these polymorphisms are associated with the atrial electrophysiologic substrate favoring reentrant mechanisms for initiation of atrial fibrillation (AF). Reentry is promoted by spatial dispersion of refractoriness that can be expressed as a coefficient of dispersion (CD).
  
  
  METHODS
  CD was calculated from the standard deviation of 12 local mean fibrillatory intervals recorded at right atrial sites during induced AF in 30 patients without structural heart disease (14 sporadic AF episodes, 16 no AF history). CD <or= 3.0 was considered normal. Cx40 genotypes were determined by DNA sequencing.
  
  
  RESULTS
  Mean CD in AF patients was 5.96 +/- 0.70 and without AF 1.59 +/- 0.18 (p < 0.001). Thirteen of fourteen patients with AF had enhanced CD. Carriers of -44 AA genotype had higher CD compared with those with -44 GG genotype (6.37 +/- 1.21 vs. 2.38 +/- 0.39, p = 0.018), whereas heterozygotes showed intermediate values (3.95 +/- 1.38, NS).
  
  
  CONCLUSIONS
  The rare linked Cx40 polymorphisms are associated with enhanced CD and thus with the substrate for reentry in AF.
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Richard N W
authors.initials: RNW
authors.lastname: Hauer
authors.forename: W Antoinette
authors.initials: WA
authors.lastname: Groenewegen
authors.forename: Mehran
authors.initials: M
authors.lastname: Firouzi
authors.forename: Hemanth
authors.initials: H
authors.lastname: Ramanna
authors.forename: Habo J
authors.initials: HJ
authors.lastname: Jongsma
mesh_terms: D000293:Adolescent; D000328:Adult; D001281:Atrial Fibrillation / Q000235:genetics* / Q000628:therapy; D002304:Cardiac Pacing, Artificial; D017630:Connexins / Q000235:genetics*; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005838:Genotype; D006325:Heart Atria / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013617:Tachycardia, Supraventricular / Q000235:genetics / Q000503:physiopathology; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D000097003:Gap Junction alpha-5 Protein