Mann, Stefan A and Otway, Robyn and Guo, Guanglan and Soka, Magdalena and Karlsdotter, Lina and Trivedi, Gunjan and Ohanian, Monique and Zodgekar, Poonam and Smith, Robert A and Wouters, Merridee A and Subbiah, Rajesh and Walker, Bruce and Kuchar, Dennis and Sanders, Prashanthan and Griffiths, Lyn and Vandenberg, Jamie I and Fatkin, Diane (2012) Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk. Journal of the American College of Cardiology, 59 (11). pp.1017-25. ISSN 1558-3597 (OA)
Full text not available from this repository.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.
(NHMRC; National Heart Foundation grants)
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Dec 2015 05:15 |
| Last Modified: | 22 Jan 2016 03:09 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/32 |
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