ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.
ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.
复制标题
DOI：
10.1161/circgen.117.001758
复制
发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Sotoodehnia N
中科院分区：
文献类型：
--
作者：
Bihlmeyer NA;Brody JA;Smith AV;Warren HR;Lin H;Isaacs A;Liu CT;Marten J;Radmanesh F;Hall LM;Grarup N;Mei H;Müller-Nurasyid M;Huffman JE;Verweij N;Guo X;Yao J;Li-Gao R;van den Berg M;Weiss S;Prins BP;van Setten J;Haessler J;Lyytikäinen LP;Li M;Alonso A;Soliman EZ;Bis JC;Austin T;Chen YI;Psaty BM;Harrris TB;Launer LJ;Padmanabhan S;Dominiczak A;Huang PL;Xie Z;Ellinor PT;Kors JA;Campbell A;Murray AD;Nelson CP;Tobin MD;Bork-Jensen J;Hansen T;Pedersen O;Linneberg A;Sinner MF;Peters A;Waldenberger M;Meitinger T;Perz S;Kolcic I;Rudan I;de Boer RA;van der Meer P;Lin HJ;Taylor KD;de Mutsert R;Trompet S;Jukema JW;Maan AC;Stricker BHC;Rivadeneira F;Uitterlinden A;Völker U;Homuth G;Völzke H;Felix SB;Mangino M;Spector TD;Bots ML;Perez M;Raitakari OT;Kähönen M;Mononen N;Gudnason V;Munroe PB;Lubitz SA;van Duijn CM;Newton-Cheh CH;Hayward C;Rosand J;Samani NJ;Kanters JK;Wilson JG;Kääb S;Polasek O;van der Harst P;Heckbert SR;Rotter JI;Mook-Kanamori DO;Eijgelsheim M;Dörr M;Jamshidi Y;Asselbergs FW;Kooperberg C;Lehtimäki T;Arking DE;Sotoodehnia N
补充数字内容可在文本中找到。通过标准ECG测量的QT间期捕获心室舒张和恢复所需的时间。JT间期是QT间期的组成部分，仅反映心室复极。QT间期延长与心脏骤停的高风险有关。我们对QT和JT间期进行了全外显子组芯片分析，包括来自Illumina Infinium HumanExome BeadChip的17341个基因中的209449种常见和罕见变异。我们在对来自23个队列的95626名个体（包括83884名欧洲血统个体，9610名黑人，1382名西班牙裔和750名亚洲人）进行的荟萃分析中，使用单变量统计模型确定了10个调节QT和JT间期的基因座，这些基因座以前未在文献中报道。这使得心室复极相关位点的总数达到45个。此外，我们使用编码变体的方法突出了17个参与心室复极的特定基因的作用，其中7个位于新的位点。我们的分析表明，肌细胞内部结构和相互联系在调节QT间期中的作用，增加了以前已知的钾，钠和钙离子调节以及自主控制的作用。我们预计，这些发现将开辟新的途径，使新的补救措施，以预防致命的室性心律失常和心脏骤停的目标。
Supplemental Digital Content is available in the text. QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.