Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.
Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.
复制标题
DOI：
10.1161/jaha.116.003644
复制
发表时间：
2016-09-13
影响因子：
5.4
通讯作者：
Makita N
中科院分区：
文献类型：
--
作者：
Yagihara N;Watanabe H;Barnett P;Duboscq-Bidot L;Thomas AC;Yang P;Ohno S;Hasegawa K;Kuwano R;Chatel S;Redon R;Schott JJ;Probst V;Koopmann TT;Bezzina CR;Wilde AA;Nakano Y;Aiba T;Miyamoto Y;Kamakura S;Darbar D;Donahue BS;Shigemizu D;Tanaka T;Tsunoda T;Suda M;Sato A;Minamino T;Endo N;Shimizu W;Horie M;Roden DM;Makita N
编码心脏Na+通道α亚基的SCN 5A编码序列的突变与各种心律失常的遗传易感性相关。SCN 5A的可变表达是导致这种多效性效应的可能机制;然而，尚不清楚SCN 5A的启动子和调节区中的变体是否也调节心律失常的风险。我们对1298例心律失常表型患者（房颤，n=444;窦房结功能障碍，n=49;传导疾病，n=133; Brugada综合征，n=583;特发性室颤，n=89）的SCN 5A核心启动子区和SCN 5A转录调控区进行了重新测序。我们在29例受各种心律失常影响的患者（房颤，n=6;窦房结功能障碍，n=1;传导疾病，n=3; Brugada综合征，n=14;特发性室颤，n=5）中确定了SCN 5A启动子的26种新的罕见变体。心律失常患者罕见变异的频率高于对照组。在与染色质免疫沉淀测序数据的比对中，大多数变体位于转录因子结合的区域。使用荧光素酶报告基因测定，对6种变体（Brugada综合征，n=3;特发性室颤，n=2;传导疾病，n=1）进行了功能表征，与野生型序列相比，每种变体均显示启动子活性降低。我们还发现了与房颤相关的调控区的罕见变异，该变异降低了启动子活性。在多种心律失常表型中鉴定了SCN 5A的核心启动子区和转录调控区的变体，这与改变的SCN 5A转录水平调节心律失常易感性的想法一致。
Mutations in the coding sequence of SCN5A, which encodes the cardiac Na+ channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild‐type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity. Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.