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

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dc.contributor.authorMann, S.
dc.contributor.authorOtway, R.
dc.contributor.authorGuo, G.
dc.contributor.authorSoka, M.
dc.contributor.authorKarlsdotter, L.
dc.contributor.authorTrivedi, G.
dc.contributor.authorOhanian, M.
dc.contributor.authorZodgekar, P.
dc.contributor.authorSmith, R.
dc.contributor.authorWouters, M.
dc.contributor.authorSubbiah, R.
dc.contributor.authorWalker, B.
dc.contributor.authorKuchar, D.
dc.contributor.authorSanders, P.
dc.contributor.authorGriffiths, L.
dc.contributor.authorVandenberg, J.
dc.contributor.authorFatkin, D.
dc.date.issued2012
dc.description.abstract<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.
dc.description.statementofresponsibilityStefan A. Mann, Robyn Otway, Guanglan Guo, Magdalena Soka, Lina Karlsdotter, Gunjan Trivedi, Monique Ohanian, Poonam Zodgekar, Robert A. Smith, Merridee A. Wouters, Rajesh Subbiah, Bruce Walker, Dennis Kuchar, Prashanthan Sanders, Lyn Griffiths, Jamie I. Vandenberg, Diane Fatkin
dc.identifier.citationJournal of the American College of Cardiology, 2012; 59(11):1017-1025
dc.identifier.doi10.1016/j.jacc.2011.11.039
dc.identifier.issn0735-1097
dc.identifier.issn1558-3597
dc.identifier.orcidSanders, P. [0000-0003-3803-8429]
dc.identifier.urihttp://hdl.handle.net/2440/72603
dc.language.isoen
dc.publisherElsevier Science Inc
dc.rightsCopyright © 2012 American College of Cardiology Foundation.
dc.source.urihttps://doi.org/10.1016/j.jacc.2011.11.039
dc.subjectatrial cell modeling
dc.subjectfamilial atrial fibrillation
dc.subjectgenetics
dc.subjectpotassium channels
dc.titleEpistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk
dc.typeJournal article
pubs.publication-statusPublished

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