Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.
J Am Coll Cardiol. 2012 Mar 13;59(11):1017-25. doi: 10.1016/j.jacc.2011.11.039.
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.
本研究旨在评估心脏 K(+) 通道基因突变在房颤（AF）家族中的作用。
K(+) 通道在心房复极中起主要作用，但心脏 K(+) 通道基因突变在 AF 家族中很少见。背景 K(+) 通道变异的综合效应，其流行程度和效应大小不一，对 AF 的心房基质影响很大，目前尚未得到充分探索。
对 80 名 AF 先证者的编码主要心脏 K(+) 通道的基因进行了重测序。在 240 名对照受试者中评估了在 AF 先证者中发现的非同义编码序列变异。使用膜片钳技术对新变异进行了特征描述，并使用 Courtemanche 心房细胞模型进行了计算机模拟。
在 9 个基因中发现了 19 个非同义变异，包括 11 个稀有变异。稀有变异在 AF 先证者中更为常见（18.8%比 4.2%，p<0.001），且变异数量平均值更大（0.21 比 0.04，p<0.001）。大多数 K(+) 通道变异单独具有适度的功能影响。评估不同人群频率的 K(+) 通道变异组合的建模模拟表明，多个电流密度的同时微小扰动具有非线性相互作用，可能导致动作电位持续时间显著（>30 ms）缩短或延长，以及复极离散度增加。
AF 家族中存在多种具有不同表型效应大小的罕见功能性 K(+) 通道基因突变，可能导致心房性心律失常的基质。心房细胞建模是评估多个变异之间上位性相互作用的有用工具。
