Mann, S.Otway, R.Guo, G.Soka, M.Karlsdotter, L.Trivedi, G.Ohanian, M.Zodgekar, P.Smith, R.Wouters, M.Subbiah, R.Walker, B.Kuchar, D.Sanders, P.Griffiths, L.Vandenberg, J.Fatkin, D.2012-08-162012-08-162012Journal of the American College of Cardiology, 2012; 59(11):1017-10250735-10971558-3597http://hdl.handle.net/2440/72603<h4>Objectives</h4>The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF).<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.enCopyright © 2012 American College of Cardiology Foundation.atrial cell modelingfamilial atrial fibrillationgeneticspotassium channelsJournal article002011732810.1016/j.jacc.2011.11.0390003012227000092-s2.0-8486323045325487Sanders, P. [0000-0003-3803-8429]