Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
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DOI:
10.1038/ng.3014
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发表时间:
2014-08
期刊:
影响因子:
30.8
通讯作者:
Newton-Cheh, Christopher
Newton-Cheh, Christopher
中科院分区:
生物学1区
文献类型:
--
作者:
Arking, Dan E.;Pulit, Sara L.;Crotti, Lia;Van der Harst, Pim;Munroe, Patricia B.;Koopmann, Tamara T.;Sotoodehnia, Nona;Rossin, Elizabeth J.;Morley, Michael;Wang, Xinchen;Johnson, Andrew D.;Lundby, Alicia;Gudbjartsson, Daniel F.;Noseworthy, Peter A.;Eijgelsheim, Mark;Bradford, Yuki;Tarasov, Kirill V.;Dorr, Marcus;Miiller-Nurasyid, Martina;Lahtinen, Annukka M.;Nolte, Ilja M.;Smith, Albert Vernon;Bis, Joshua C.;Isaacs, Aaron;Newhouse, Stephen J.;Evans, Daniel S.;Post, Wendy S.;Waggott, Daryl;Lyytikainen, Leo-Pekka;Hicks, Andrew A.;Eisele, Lewin;Ellinghaus, David;Hayward, Caroline;Navarro, Pau;Ulivi, Sheila;Tanaka, Toshiko;Tester, David J.;Chatel, Stephanie;Gustafsson, Stefan;Kumari, Meena;Morris, Richard W.;Naluai, Asa T.;Padmanabhan, Sandosh;Kluttig, Alexander;Strohmer, Bernhard;Panayiotou, Andrie G.;Torres, Maria;Knoflach, Michael;Hubacek, Jaroslav A.;Slowikowski, Kamil;Raychaudhuri, Soumya;Kumar, Runjun D.;Harris, Tamara B.;Launer, Lenore J.;Shuldiner, Alan R.;Alonso, Alvaro;Bader, Joel S.;EhreT, Georg;Huang, Hailiang;Kao, W. H. Linda;Strait, James B.;Macfarlane, Peter W.;Brown, Morris;Caulfield, Mark J.;Samani, Nilesh J.;Kronenberg, Florian;Willeit, Johann;Smith, J. Gustav;Greiser, Karin H.;Schwabedissen, Henriette Meyer Zu;Werdan, Karl;Carella, Massimo;Zelante, Leopoldo;Heckbert, Susan R.;Psaty, Bruce M.;Rotter, Jerome I.;Kolcic, Ivana;Poagek, Ozren;Wright, Alan F.;Griffin, Maura;Daly, Mark J.;Arnar, David O.;Holm, Hilma;Thorsteinsdottir, Unnur;Denny, Joshua C.;Roden, Dan M.;Zuvich, Rebecca L.;Emilsson, Valur;Plump, Andrew S.;Larson, Martin G.;O'Donnell, Christopher J.;Yin, Xiaoyan;Bobboll, Marco;D'Adamo, Adamo P.;Iorio, Annamaria;Sinagra, Gianfranco;Carracedo, Angel;Cummings, Steven R.;Nalls, Michael A.;Jula, Antti;Kontula, Kimmo K.;Marjamaa, Annukka;Oikarinen, Lasse;Perola, Markus;Porthan, Kimmo;Erbe, Raimund;Hoffmann, Per;Jockel, Karl-Heinz;Kalsch, Hagen;Nothen, Markus M.;Den Hoed, Marcel;Loos, Ruth J. F.;Thelle, Dag S.;Gieger, Christian;Meitinger, Thomas;Perz, Siegfried;Peters, Annette;Pruchal, Hanna;Sinner, Moritz F.;Waldenberger, Melanie;De Boer, Rudolf A.;Franke, Lude;Van der Vleuten, Pieter A.;Beckmann, Britt Maria;Martens, Eimo;Bardail, Abdennasser;Hofman, Nynke;Wilde, Arthur A. M.;Behr, Elijah R.;Dalageorgou, Chrysoula;Giudicessi, John R.;Medeiros-Domingo, Argelia;Barc, Julien;Kyndt, Florence;Probst, Vincent;Ghidoni, Alice;Insolia, Roberto;Hamilton, Robert M.;Scherer, Stephen W.;Brandimarto, Jeffrey;Margulies, Kenneth;Moravec, Christine E.;Del Greco, Fabiola;Fuchsberger, Christian;O'Connell, Jeffrey R.;Lee, Wai K.;Watt, Graham C. M.;Campbell, Harry;Wild, Sarah H.;El Mokhtari, Nour E.;Frey, Norbert;Asselbergs, Folkert W.;Leach, Irene Mateo;Navis, Gerjan;Van den Berg, Maarten P.;Van Veldhuisen, Dirk J.;Kellis, Manolis;Krijthe, Bouwe P.;Franco, Oscar H.;Hofman, Albert;Kors, Jan A.;Uitterlinden, Andre G.;Witteman, Jacqueline C. M.;Kedenko, Lyudmyla;Lamina, Claudia;Oostra, Ben A.;Abecasis, Goncalo R.;Lakatta, Edward G.;Mulas, Antonella;Orru, Marco;Schlessinger, David;Uda, Manuela;Markus, Marcello R. P.;Volker, Uwe;Snieder, Harold;Spector, Timothy D.;Arnlov, Johan;Lind, Lars;Sundstrom, Johan;Syvanen, Ann-Christine;Kivimaki, Mika;Kahonen, Mika;Mononen, Nina;Raitakari, I. T.;Viikari, Jorma S.;Adamkova, Vera;Kiech, Stefan;Brion, Maria;Nicolaides, Andrew N.;Paulweber, Bernhard;Haerting, Johannes;Dominiczak, Anna F.;Nyberg, Fredrik;Whincup, Peter H.;Hingorani, Aroon D.;Schott, Jean-Jacques;Bezzina, Connie R.;Ingelsson, Erik;Ferrucci, Luigi;Gaspariniin, Paolo;Wilson, James F.;Rudan, Igor;Franke, Andre;Miihleisen, Thomas W.;Pramstaller, Peter P.;Lehtimaki, Terho J.;Paterson, Andrew D.;Parsa, Afshin;Liu, Yongmei;Van Duijn, Cornelia M.;Siscovick, David S.;Gudnason, Vilmundur;Jamshidi, Yalda;Salomaa, Veikko;Felix, Stephan B.;Sanna, Serena;Ritchie, Marylyn D.;Stricker, Bruno H.;Stefansson, Karl;Boyer, Laurie A.;Cappola, Thomas P.;Olsen, Jesper V.;Lage, Kasper;Schwartz, Peter J.;Kaab, Stefan;Chakravarti, Aravinda;Ackerman, Michael J.;Pfeufer, Arne;De Bakker, Paul I. W.;Newton-Cheh, Christopher

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QT间期是反映心肌复极的心电图指标,是一种遗传性状。QT间期延长是室性心律失常和心源性猝死(SCD)的危险因素,并可能表明存在潜在致命的孟德尔长QT综合征(LQTS)。通过对多达100,000人进行全基因组关联和复制研究,我们确定了35个常见的QT间期变异位点,这些位点共同解释了108 -10%的QT变异,并强调了钙调节在心肌复极中的重要性。对298例不相关的LQTS先证者的6个新QT位点进行罕见变异分析,发现了对照组中未发现的编码变异,但因果关系不确定,因此需要验证。几个新发现的基因座编码的蛋白质与其他公认的复极蛋白的物理相互作用。我们的整合常见的变异关联,表达和正交蛋白质-蛋白质相互作用的屏幕提供了新的见解心脏电生理学和识别室性心律失常,LQTS和SCD的新的候选基因。
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
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