Key result
Rare cardiac potassium channel variants occur ~4.5x more often in AF patients than controls.
Why the study?
Single mutations in cardiac K(+) channel genes are infrequently present in AF families, and the collective effect of background K(+) channel variants on the atrial substrate for AF remains largely unexplored.
Do rare functional cardiac K(+) channel gene variants increase the risk of atrial fibrillation and alter atrial repolarization?
Case-Control (n=320)
Do rare functional cardiac K(+) channel gene variants increase the risk of atrial fibrillation and alter atrial repolarization?
Families with atrial fibrillation have an excess of rare functional potassium channel gene variants that interact epistatically to alter atrial repolarization and create an arrhythmogenic substrate.
Answers are grounded in this paper and cite their sources.
Collective K+ channel variant burden may shape familial AF substrate; leaves open any role in risk stratification or targeted therapy.
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.
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Mann et al. (2012) conducted a case-control in Atrial fibrillation (n=320). Atrial fibrillation vs. Control subjects was evaluated on Frequency of rare nonsynonymous K(+) channel gene variants (p=<0.001). Atrial fibrillation probands had a significantly higher frequency of rare cardiac potassium channel gene variants compared to control subjects (18.8% vs. 4.2%, p < 0.001).
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