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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Wednesday,2015-03-04 11:49 America/Los_Angeles — zdrager
| Title | Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Arking, DE, Pulit, SL, Crotti, L, van der Harst, P, Munroe, PB, Koopmann, TT, Sotoodehnia, N, Rossin, EJ, Morley, M, Wang, X, Johnson, AD, Lundby, A, Gudbjartsson, DF, Noseworthy, PA, Eijgelsheim, M, Bradford, Y, Tarasov, KV, Dörr, M, Müller-Nurasyid, M, Lahtinen, AM, Nolte, IM, Smith, AVernon, Bis, JC, Isaacs, A, Newhouse, SJ, Evans, DS, Post, WS, Waggott, D, Lyytikäinen, L-P, Hicks, AA, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, DJ, Chatel, S, Gustafsson, S, Kumari, M, Morris, RW, Naluai, ÅT, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, AG, Torres, M, Knoflach, M, Hubacek, JA, Slowikowski, K, Raychaudhuri, S, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Alonso, A, Bader, JS, Ehret, G, Huang, H, Kao, LWH, Strait, JB, Macfarlane, PW, Brown, M, Caulfield, MJ, Samani, NJ, Kronenberg, F, Willeit, J, J Smith, G, Greiser, KH, Schwabedissen, HMeyer Zu, Werdan, K, Carella, M, Zelante, L, Heckbert, SR, Psaty, BM, Rotter, JI, Kolcic, I, Polasek, O, Wright, AF, Griffin, M, Daly, MJ, Arnar, DO, Holm, H, Thorsteinsdottir, U, Denny, JC, Roden, DM, Zuvich, RL, Emilsson, V, Plump, AS, Larson, MG, O'Donnell, CJ, Yin, X, Bobbo, M, D'Adamo, AP, Iorio, A, Sinagra, G, Carracedo, A, Cummings, SR, Nalls, MA, Jula, A, Kontula, KK, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K-H, Kälsch, H, Nöthen, MM, Hoed, Mden, Loos, RJF, Thelle, DS, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, MF, Waldenberger, M, de Boer, RA, Franke, L, van der Vleuten, PA, Beckmann, BMaria, Martens, E, Bardai, A, Hofman, N, Wilde, AAM, Behr, ER, Dalageorgou, C, Giudicessi, JR, Medeiros-Domingo, A, Barc, J, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, RM, Scherer, SW, Brandimarto, J, Margulies, K, Moravec, CE, M, Fdel Greco, Fuchsberger, C, O'Connell, JR, Lee, WK, Watt, GCM, Campbell, H, Wild, SH, Mokhtari, NEEl, Frey, N, Asselbergs, FW, Leach, IMateo, Navis, G, van den Berg, MP, van Veldhuisen, DJ, Kellis, M, Krijthe, BP, Franco, OH, Hofman, A, Kors, JA, Uitterlinden, AG, Witteman, JCM, Kedenko, L, Lamina, C, Oostra, BA, Abecasis, GR, Lakatta, EG, Mulas, A, Orrù, M, Schlessinger, D, Uda, M, Markus, MRP, Völker, U, Snieder, H, Spector, TD, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A-C, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, OT, Viikari, JS, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, AN, Paulweber, B, Haerting, J, Dominiczak, AF, Nyberg, F, Whincup, PH, Hingorani, AD, Schott, J-J, Bezzina, CR, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, JF, Rudan, I, Franke, A, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, Parsa, A, Liu, Y, van Duijn, CM, Siscovick, DS, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, SB, Sanna, S, Ritchie, MD, Stricker, BH, Stefansson, K, Boyer, LA, Cappola, TP, Olsen, JV, Lage, K, Schwartz, PJ, Kääb, S, Chakravarti, A, Ackerman, MJ, Pfeufer, A, de Bakker, PIW, Newton-Cheh, C |
| Corporate/Institutional Authors | CARe Consortium,, COGENT Consortium, DCCT/EDIC, eMERGE Consortium, HRGEN Consortium |
| Journal | Nat Genet |
| Volume | 46 |
| Issue | 8 |
| Pagination | 826-36 |
| Date Published | 2014 Aug |
| ISSN | 1546-1718 |
| Keywords | Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide |
| Abstract | <p>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 loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD. </p> |
| DOI | 10.1038/ng.3014 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 24952745 |
| PubMed Central ID | PMC4124521 |
| Grant List | R01 GM104469 / GM / NIGMS NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom G9521010 / / Medical Research Council / United Kingdom U01 DK094176 / DK / NIDDK NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01 HG004037 / HG / NHGRI NIH HHS / United States T32 HG002295 / HG / NHGRI NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States R01 HL098283 / HL / NHLBI NIH HHS / United States UL1 TR000114 / TR / NCATS NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States MC_UU_12015/1 / / Medical Research Council / United Kingdom R01 HL105756 / HL / NHLBI NIH HHS / United States MC_U106179471 / / Medical Research Council / United Kingdom P30 DK063491 / DK / NIDDK NIH HHS / United States R01 HL105993 / HL / NHLBI NIH HHS / United States P30 DK072488 / DK / NIDDK NIH HHS / United States MC_PC_U127592696 / / Medical Research Council / United Kingdom G0701863 / / Medical Research Council / United Kingdom MC_PC_U127561128 / / Medical Research Council / United Kingdom UL1 TR000142 / TR / NCATS NIH HHS / United States MR/K006584/1 / / Medical Research Council / United Kingdom MR/K013351/1 / / Medical Research Council / United Kingdom RG/13/16/30528 / / British Heart Foundation / United Kingdom R01 HL117626 / HL / NHLBI NIH HHS / United States R01 HL113933 / HL / NHLBI NIH HHS / United States K23 HL080025 / HL / NHLBI NIH HHS / United States PG/12/38/29615 / / British Heart Foundation / United Kingdom R01 HL111267 / HL / NHLBI NIH HHS / United States RG/10/12/28456 / / British Heart Foundation / United Kingdom |