De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia.
De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia.
复制标题
De Novo FGF12（成纤维细胞生长因子 12）功能变异可能与特发性室性心动过速相关
DOI：
10.1161/jaha.117.006130
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发表时间：
2017-08-03
影响因子：
5.4
通讯作者：
Tu X
中科院分区：
文献类型：
--
作者：
Li Q;Zhao Y;Wu G;Chen S;Zhou Y;Li S;Zhou M;Fan Q;Pu J;Hong K;Cheng X;Kenneth Wang Q;Tu X
背景特发性室性心动过速(VT)是一种发生在心脏结构正常的心律失常。特发性室上性心动过速的遗传性尚不清楚，导致特发性室上性心动过速发生的众多遗传因素也尚不清楚。FGF12(成纤维细胞生长因子12)在室性心动过速的遗传发病机制中可能起重要作用。方法与结果我们在2个独立的中国队列中验证了FGF12基因变异与室性心动过速相关的假设，并对320例无血缘关系的特发性室上性心动过速患者的FGF12基因的所有外显子、外显子-内含子边界以及5‘和3’非翻译区进行了重新测序。在基于人群的病例对照关联研究中，我们选择了3个单核苷酸多态：rs1460922、rs4687326和rs2686464，它们包含了FGF12的所有外显子。结果显示，在调整性别和年龄因素后，FGF12的单核苷酸多态rs1460922与室性心动过速显著相关：在发现样本中校正P=0.015(优势比：1.5 4[95%CI，1.0 9~2.19])，在复制样本中校正P=0.018(优势比：1.6 4[95%CI，1.0 9~2.48])，在合并样本中校正P=2.5 2 E-0 4(优势比：1.5 9[95%CI，1.2 4~2.0 3])。在对FGF12的所有氨基酸编码区和非翻译区重新测序后，发现了5个罕见的变异。Western blotting结果显示，在163例右室流出道室性心动过速患者中，新发现的功能变异p.P211Q可显著下调FGF12的表达(1.84%)。结论在本研究中，我们观察到FGF12的rs1460922与室性心动过速密切相关，FGF12的从头变异可能是室性心动过速发生的重要遗传危险因素。
Background Idiopathic ventricular tachycardia (VT) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in FGF12 (fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na+ channel NaV1.5, may play an important role in the genetic pathogenesis of VT. Methods and Results We tested the hypothesis that genetic variations in FGF12 are associated with VT in 2 independent Chinese cohorts and resequenced all the exons and exon–intron boundaries and the 5′ and 3′ untranslated regions of FGF12 in 320 unrelated participants with idiopathic VT. For population‐based case–control association studies, we chose 3 single‐nucleotide polymorphisms—rs1460922, rs4687326, and rs2686464—which included all the exons of FGF12. The results showed that the single‐nucleotide polymorphism rs1460922 in FGF12 was significantly associated with VT after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted P=0.015 (odds ratio: 1.54 [95% CI, 1.09–2.19]) in the discovery sample, adjusted P=0.018 (odds ratio: 1.64 [95% CI, 1.09–2.48]) in the replication sample, and adjusted P=2.52E‐04 (odds ratio: 1.59 [95% CI, 1.24–2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of FGF12, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate FGF12 expression significantly. Conclusions In this study, we observed that rs1460922 of FGF12 was significantly associated with VT and identified that a de novo variation of FGF12 may be an important genetic risk factor for the pathogenesis of VT.