title: Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk.
abstract: OBJECTIVE
  The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF).
  
  
  BACKGROUND
  The K(+) channels play a major role in atrial repolarization but single mutations in cardiac K(+) channel genes are infrequently present in AF families. The collective effect of background K(+) channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored.
  
  
  METHODS
  Genes encoding the major cardiac K(+) channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model.
  
  
  RESULTS
  Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K(+) channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K(+) channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization.
  
  
  CONCLUSIONS
  Families with AF show an excess of rare functional K(+) channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.
authors.affiliation: Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Mann
authors.forename: Robyn
authors.initials: R
authors.lastname: Otway
authors.forename: Guanglan
authors.initials: G
authors.lastname: Guo
authors.forename: Magdalena
authors.initials: M
authors.lastname: Soka
authors.forename: Lina
authors.initials: L
authors.lastname: Karlsdotter
authors.forename: Gunjan
authors.initials: G
authors.lastname: Trivedi
authors.forename: Monique
authors.initials: M
authors.lastname: Ohanian
authors.forename: Poonam
authors.initials: P
authors.lastname: Zodgekar
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: Merridee A
authors.initials: MA
authors.lastname: Wouters
authors.forename: Rajesh
authors.initials: R
authors.lastname: Subbiah
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.forename: Dennis
authors.initials: D
authors.lastname: Kuchar
authors.forename: Prashanthan
authors.initials: P
authors.lastname: Sanders
authors.forename: Lyn
authors.initials: L
authors.lastname: Griffiths
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D015221:Potassium Channels