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

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

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  • 1Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.



The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF).


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.


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.


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.


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.

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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