Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk

J Am Coll Cardiol. 2012 Mar 13;59(11):1017-25. doi: 10.1016/j.jacc.2011.11.039.

Abstract

Objectives: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Atrial Fibrillation / genetics*
  • Case-Control Studies
  • Epistasis, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heart Conduction System / physiology
  • Humans
  • Male
  • Middle Aged
  • Patch-Clamp Techniques
  • Potassium Channels / genetics*
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • Potassium Channels