SCN5A encodes the voltage-gated Na⁺ channel Na_V1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure–related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.

中文翻译：

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一个常见的变异改变了 SCN5A-miR-24 的相互作用并与心力衰竭死亡率相关

SCN5A编码负责心脏动作电位去极化和快速细胞间传导的电压门控 Na ⁺通道 Na _{V 1.5。}破坏SCN5A编码序列的突变会导致遗传性心律失常和心肌病，以及与SCN5A剪接、定位和与心力衰竭相关的心源性猝死相关的功能相关的单核苷酸多态性 (SNP) 。然而，调节SCN5A的 SNP 的临床相关性表达水平仍有待研究。我们最近生成了人类心脏中 microRNA (miR) 结合位点的全转录组图谱，评估了它们与常见 SNP 的重叠，并确定了与SCN5A编码序列中的 miR-24 位点相邻的同义 SNP (rs1805126) 。该 SNP 先前被证明与心脏电生理参数可重复相关，但不被认为是因果关系。在这里，我们表明 miR-24 有效抑制SCN5A表达，而 rs1805126 调节这种调节。我们发现 rs1805126 次要等位基因与心脏SCN5A减少有关表达和次要等位基因纯合子心力衰竭受试者的射血分数降低和死亡率增加，但不增加室性快速性心律失常。在小鼠中，我们发现了降低Scn5a表达导致心肌活性氧物质积累的潜在基础。总之，这些数据重申了考虑同义 SNP 与 miR 和疾病相关的机械意义的重要性，并强调了SCN5A表达与心力衰竭中的非心律失常性死亡之间的惊人联系。