Significant association of rare variant p.Gly8Ser in cardiac sodium channel beta4-subunit SCN4B with atrial fibrillation.
Significant association of rare variant p.Gly8Ser in cardiac sodium channel beta4-subunit SCN4B with atrial fibrillation.
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心脏钠通道β4亚基SCN4B中罕见变异p.Gly8Ser与心房颤动的显着相关性。
DOI：
10.1111/ahg.12305
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发表时间：
2019
影响因子：
1.9
通讯作者：
Zhang Rong
中科院分区：
文献类型：
--
作者：
Xiong Hongbo;Yang Qin;Zhang Xiaoping;Wang Pengxia;Chen Feifei;Liu Ying;Wang Pengyun;Zhao Yuanyuan;Li Sisi;Huang Yufeng;Chen Shanshan;Wang Xiaojing;Zhang Hongfu;Yu Dong;Tan Chencheng;Fang Cheng;Huang Yuan;Wu Gang;Wu Yanxia;Cheng Xiang;Liao Yuhua;Zhang Rong
房颤（AF）影响全球3350万人。它占中风的15%，并增加心力衰竭和猝死的风险。电压门控心脏钠通道复合物负责心脏动作电位的产生和传导，由主要的成孔α亚基Nav1.5（由SCN 5A基因编码）和一个或多个辅助β亚基组成，包括分别由SCN 1B至SCN 4 B编码的Navβ1至Navβ4。我们和其他人在AF患者中发现了SCN 1和SCN 2的功能丧失突变和SCN 3的显性阴性突变。在散发性AF患者和小核心家族中发现了SCN 4 B的三种错义突变;然而，SCN 4 B突变与AF之间的关系仍有待进一步确定。在这项研究中，我们对477例AF患者进行了SCN 4 B突变分析，并在4例患者中发现了一个非同义基因组变体p.Gly8Ser。为了评估p.Gly8Ser变异与AF之间的关联，我们对两个独立人群进行了病例对照关联研究（第一个发现人群中有944例AF患者与9，81例非AF对照，第二个重复人群中有732例病例与1，291例对照）。在两个独立人群和合并人群中，p.Gly8Ser与普通AF以及孤立性AF（p= 0.018，OR = 2.85）之间存在显著相关性（p= 4.16 × 10−4，比值比[OR] = 3.14）。这些数据表明，SCN 4 B的罕见变异p.Gly8Ser与AF的发生有显著的危险性，SCN 4 B是AF的一个候选易感基因。
Atrial fibrillation (AF) affects 33.5 million individuals worldwide. It accounts for 15% of strokes and increases risk of heart failure and sudden death. The voltage‐gated cardiac sodium channel complex is responsible for the generation and conduction of the cardiac action potential, and composed of the main pore‐forming α‐subunit Nav1.5 (encoded by theSCN5Agene) and one or more auxiliary β‐subunits, including Navβ1 to Navβ4 encoded bySCN1BtoSCN4B, respectively. We and others identified loss‐of‐function mutations inSCN1BandSCN2Band dominant‐negative mutations inSCN3Bin patients with AF. Three missense variants inSCN4Bwere identified in sporadic AF patients and small nuclear families; however, the association betweenSCN4Bvariants and AF remains to be further defined. In this study, we performed mutational analysis inSCN4Busing a panel of 477 AF patients, and identified one nonsynonymous genomic variant p.Gly8Ser in four patients. To assess the association between the p.Gly8Ser variant and AF, we carried out case‐control association studies with two independent populations (944 AF patients vs. 9,81 non‐AF controls in the first discovery population and 732 cases and 1,291 controls in the second replication population). Significant association was identified in the two independent populations and in the combined population (p= 4.16 × 10−4, odds ratio [OR] = 3.14) between p.Gly8Ser and common AF as well as lone AF (p= 0.018, OR = 2.85). These data suggest that rare variant p.Gly8Ser ofSCN4Bconfers a significant risk of AF, andSCN4Bis a candidate susceptibility gene for AF.