特发性室性快速心律失常的全基因组关联研究确定了[具体内容缺失]在钙稳态和心律维持中的关键作用。
Genome-Wide Association Study for Idiopathic Ventricular Tachyarrhythmias Identifies Key Role of and in Calcium Homeostasis and Cardiac Rhythm Maintenance.
作者信息
Fang Chen, Wang Pengxia, Yu Dong, Zhang Xiaoyu, Gou Dongzhi, Liang Lina, Bai Xuemei, Xie Wen, Li Hui, Pu Jielin, Yao Yufeng, Wang Binbin, Ren Xiang, Ke Tie, Tu Xin, Xu Chengqi, Wang Qing K
机构信息
The Center for Human Genome Research, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan (C.F., P.W., D.Y., X.Z., D.G.,L.L., X.B., W.X., H.L., Y.Y., X.R., T.K., X.T., C.X., Q.K.W.).
Department of Cardiology, East Hospital, Tongji University, Shanghai (J.P.).
出版信息
Circ Genom Precis Med. 2022 Oct;15(5):e003603. doi: 10.1161/CIRCGEN.121.003603. Epub 2022 Jul 27.
BACKGROUND
Idiopathic ventricular tachycardia (VT) occurs in structurally normal hearts and accounts for a significant number of all types of VT. The genome-wide association study is the most effective strategy for identifying novel genetic variants for common diseases. However, no genome-wide association study has been reported for idiopathic VT.
METHODS
We conducted the first genome-wide association study for idiopathic VT in the Chinese Han population using a discovery population with 246 cases and 648 controls and a replication population with 222 cases and >4072 controls. Candidate VT genes were functionally characterized in zebrafish. Real-time RT-PCR analysis was used to determine the effects of candidate genes on expression of ion channels and regulators. Patch-clamping was used to record L-type calcium current from neonatal rat cardiomyocytes with overexpression of candidate genes.
RESULTS
We identified 4 significant loci represented by rs78960694 (minor allele frequency [MAF]=5.02% in cases and 1.84% in controls; =4.30×1012, odds ratio [OR]=3.91) and rs2229095 (MAF=3.25% in cases and 1.63% in controls; =1.02×107, OR=3.44) near and in , respectively, rs68126098 in (MAF=40.98% in cases and 32.07% in controls; 2.40×108, OR=1.53), rs2390325 between and (MAF=21.19% in cases and 15.12% in controls; =1.92×107, OR=1.62), and rs270065 in (MAF=33.63% in cases and 40.25% in controls; =9.51×107, OR=0.69). Note that the associations of idiopathic VT for variant rs78960694 and variant rs68126098 reach genome-wide significance (<5.00×108). Overexpression of either or increased the heart rate in zebrafish, and enhanced expression of , or in zebrafish embryos, HEK293, and AC16 cardiomyocytes. Overexpression of either or significantly increased L-type Ca2+ current density.
CONCLUSIONS
The first genome-wide association study identifies 4 novel loci and 2 risk genes ( and ) for idiopathic VT. These findings identify new molecular determinants for cardiac calcium homeostasis and rhythm maintenance and provide novel targets for diagnosis and treatment for idiopathic VT.
背景
特发性室性心动过速（VT）发生于结构正常的心脏，在所有类型的室性心动过速中占相当比例。全基因组关联研究是识别常见疾病新基因变异的最有效策略。然而，尚无关于特发性室性心动过速的全基因组关联研究报道。
方法
我们在中国汉族人群中开展了首例特发性室性心动过速的全基因组关联研究，使用了一个包含246例病例和648例对照的发现队列以及一个包含222例病例和超过4072例对照的重复队列。在斑马鱼中对候选室性心动过速基因进行功能表征。采用实时逆转录聚合酶链反应分析来确定候选基因对离子通道和调节因子表达的影响。使用膜片钳技术记录过表达候选基因的新生大鼠心肌细胞的L型钙电流。
结果
我们确定了4个显著位点，分别由rs78960694（病例中的次要等位基因频率[MAF]=5.02%，对照中的MAF=1.84%；=4.30×1012，比值比[OR]=3.91）和rs2229095（病例中的MAF=3.25%，对照中的MAF=1.63%；=1.02×107，OR=3.44）代表，分别位于附近和内部，位于的rs68126098（病例中的MAF=40.98%，对照中的MAF=32.07%；2.40×108，OR=1.53），位于和之间的rs2390325（病例中的MAF=21.19%，对照中的MAF=15.12%；=1.92×107，OR=1.62），以及位于的rs270065（病例中的MAF=33.63%，对照中的MAF=40.25%；=9.51×107，OR=0.69）。注意，特发性室性心动过速与变体rs78960694和变体rs68126098的关联达到全基因组显著性（<5.00×108）。过表达或均可增加斑马鱼的心率，并增强斑马鱼胚胎、人胚肾293细胞和AC16心肌细胞中、或的表达。过表达或均显著增加L型Ca2+电流密度。
结论
首例全基因组关联研究确定了特发性室性心动过速的4个新位点和2个风险基因（和）。这些发现确定了心脏钙稳态和节律维持的新分子决定因素，并为特发性室性心动过速的诊断和治疗提供了新靶点。
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