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8 results on '"Dalageorgou, Chrysoula"'

1. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

Author

Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, Dalageorgou C, Zorio E, Domingo D, Murday V, Findlay I, Duncan A, Carr-White G, Robert L, Bueser T, Langman C, Fynn SP, Goddard M, White A, Bundgaard H, Ferrero-Miliani L, Wheeldon N, Suvarna SK, O'Beirne A, Lowe MD, McKenna WJ, Elliott PM, and Lambiase PD

Subjects
Adolescent, Adult, Autopsy, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Death, Sudden, Cardiac prevention & control, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Testing, Humans, Infant, Male, Middle Aged, Mutation, NAV1.5 Voltage-Gated Sodium Channel genetics, Pedigree, Sequence Analysis, DNA, United Kingdom, Young Adult, Brugada Syndrome diagnosis, Brugada Syndrome genetics, Exome genetics, Long QT Syndrome diagnosis, Long QT Syndrome genetics
Abstract

Aims: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible., Methods and Results: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands., Conclusion: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Published
2016
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2. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Author

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 AV, Bis JC, Isaacs A, Newhouse SJ, Evans DS, Post WS, Waggott D, Lyytikäinen LP, 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 WH, Strait JB, Macfarlane PW, Brown M, Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, Smith JG, Greiser KH, Meyer Zu Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert SR, Psaty BM, Rotter JI, Kolcic I, Polašek O, Wright AF, Griffin M, Daly MJ, Arnar DO, Hólm 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 KH, Kälsch H, Nöthen MM, den Hoed M, Loos RJ, 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 BM, Martens E, Bardai A, Hofman N, Wilde AA, 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, del Greco M F, Fuchsberger C, O'Connell JR, Lee WK, Watt GC, Campbell H, Wild SH, El Mokhtari NE, Frey N, Asselbergs FW, Mateo Leach I, Navis G, van den Berg MP, van Veldhuisen DJ, Kellis M, Krijthe BP, Franco OH, Hofman A, Kors JA, Uitterlinden AG, Witteman JC, Kedenko L, Lamina C, Oostra BA, Abecasis GR, Lakatta EG, Mulas A, Orrú M, Schlessinger D, Uda M, Markus MR, Völker U, Snieder H, Spector TD, Ärnlöv J, Lind L, Sundström J, Syvänen AC, 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 JJ, 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 PI, and Newton-Cheh C

Subjects
Adult, Aged, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism, Death, Sudden, Cardiac etiology, Electrocardiography methods, Female, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Genotype, Heart Ventricles metabolism, Humans, Long QT Syndrome metabolism, Male, Middle Aged, Myocardium metabolism, Polymorphism, Single Nucleotide, Calcium Signaling genetics, Long QT Syndrome genetics
Abstract

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.

Published
2014
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3. Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia.

Author

Jamshidi Y, Nolte IM, Dalageorgou C, Zheng D, Johnson T, Bastiaenen R, Ruddy S, Talbott D, Norris KJ, Snieder H, George AL, Marshall V, Shakir S, Kannankeril PJ, Munroe PB, Camm AJ, Jeffery S, Roden DM, and Behr ER

Subjects
Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Long QT Syndrome genetics, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Torsades de Pointes genetics, Ventricular Fibrillation genetics, Young Adult, Adaptor Proteins, Signal Transducing genetics, Amiodarone adverse effects, Anti-Arrhythmia Agents adverse effects, Long QT Syndrome chemically induced, Torsades de Pointes chemically induced, Ventricular Fibrillation chemically induced
Abstract

Objectives: This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS)., Background: Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS., Methods: This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study., Results: The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4))., Conclusions: These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Published
2012
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4. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

Author

Kääb S, Crawford DC, Sinner MF, Behr ER, Kannankeril PJ, Wilde AA, Bezzina CR, Schulze-Bahr E, Guicheney P, Bishopric NH, Myerburg RJ, Schott JJ, Pfeufer A, Beckmann BM, Martens E, Zhang T, Stallmeyer B, Zumhagen S, Denjoy I, Bardai A, Van Gelder IC, Jamshidi Y, Dalageorgou C, Marshall V, Jeffery S, Shakir S, Camm AJ, Steinbeck G, Perz S, Lichtner P, Meitinger T, Peters A, Wichmann HE, Ingram C, Bradford Y, Carter S, Norris K, Ritchie MD, George AL Jr, and Roden DM

Subjects
Aged, Aged, 80 and over, Alleles, Amino Acid Substitution, Case-Control Studies, Cohort Studies, Female, Genotype, Haplotypes, Humans, Long QT Syndrome genetics, Male, Middle Aged, Odds Ratio, Potassium blood, Anti-Arrhythmia Agents adverse effects, Long QT Syndrome drug therapy, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated genetics, Torsades de Pointes chemically induced, Torsades de Pointes genetics
Abstract

Background: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS., Methods and Results: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects., Conclusions: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Published
2012
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5. Long-QT syndrome and torsades de pointes in a patient with Takotsubo cardiomyopathy: an unusual case.

Author

Mahida S, Dalageorgou C, and Behr ER

Subjects
Female, Humans, Middle Aged, Rare Diseases diagnosis, Long QT Syndrome diagnosis, Takotsubo Cardiomyopathy diagnosis, Torsades de Pointes diagnosis
Abstract

Takotsubo cardiomyopathy is a syndrome characterized by transient left ventricular apical ballooning associated with electrocardiogram (ECG) changes and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without significant coronary disease at angiography. We report an unusual case of a patient who presented with Takotsubo cardiomyopathy associated with long-QT syndrome and who developed cardiac arrest secondary to torsades de pointes.The relationship between Takotsubo cardiomyopathy and abnormal repolarization has been well documented. Despite this, there have been few reports of malignant ventricular arrhythmias or sudden death. This report suggests that prolongation of QTc interval in Takotsubo cardiomyopathy may not be as benign as previously suggested but may in fact uncover an abnormality of repolarization that may be genetic in basis and carry a risk of sudden death.

Published
2009
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6. Heritability of QT interval: how much is explained by genes for resting heart rate?

Author

Dalageorgou C, Ge D, Jamshidi Y, Nolte IM, Riese H, Savelieva I, Carter ND, Spector TD, and Snieder H

Subjects
Female, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Humans, Male, Middle Aged, Netherlands epidemiology, Prevalence, Risk Factors, Electrocardiography statistics & numerical data, Heart Rate genetics, Long QT Syndrome epidemiology, Long QT Syndrome genetics, Quantitative Trait, Heritable, Risk Assessment methods, Twins
Abstract

Introduction: Objective of this study was to determine the optimal (most heritable) phenotype for gene finding studies of QT interval in the general population. We also studied the extent to which heritability of QT interval can be explained by genes that also influence resting heart rate., Methods and Results: Subjects in this classic twin study were 105 monozygotic and 256 dizygotic female twin pairs (mean age: 49.9 +/- 11.5). ECG parameters were measured electronically using the Cardiofax ECG-9020. Quantitative genetic modeling was performed with Mx software. Best-fitting univariate models showed significant heritabilities for resting heart rate (0.55, 95% CI: 0.44-0.65), uncorrected QT interval (0.60, 95% CI: 0.49-0.69), and the Framingham QTc interval (0.50, 95% CI: 0.39-0.60). Familial resemblance of Bazett's QTc was best explained by shared environmental factors (0.34, 95% CI: 0.24-0.43) rather than genes. Simultaneously modeling heart rate and the uncorrected QT interval confirmed considerable heritabilities of 56% and 60%, respectively. Forty-four percent of the variance in QT interval was due to genes in common with heart rate, whereas 16% was due to genes specific to QT interval. The heritability of QT interval after the removal of effects shared with heart rate within the bivariate model (cf. QTc) was 51%., Conclusion: About a quarter of the QT interval heritability is due to genes specific for QT interval, while the majority is shared with genes for heart rate. Differences in QTc heritability estimates indicate that use of correction formulae is best avoided in gene finding studies to avoid erroneous results.

Published
2008
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7. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

Author

Nunn, Laurence M., Lopes, Luis R., Syrris, Petros, Murphy, Cian, Plagnol, Vincent, Firman, Eileen, Dalageorgou, Chrysoula, Zorio, Esther, Domingo, Diana, Murday, Victoria, Findlay, Iain, Duncan, Alexis, Carr-White, Gerry, Robert, Leema, Bueser, Teofila, Langman, Caroline, Fynn, Simon P., Goddard, Martin, White, Anne, and Bundgaard, Henning

Subjects
CARDIAC arrest prevention, LONG QT syndrome diagnosis, BRUGADA syndrome diagnosis, AUTOPSY, COMPARATIVE studies, DISEASE susceptibility, GENEALOGY, GENES, GENETIC techniques, GENOMES, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, GENETIC mutation, RESEARCH, GENETIC testing, LONG QT syndrome, EVALUATION research, BRUGADA syndrome, CASE-control method, SEQUENCE analysis, MEMBRANE transport proteins
Abstract

Aims: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.Methods and Results: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands.Conclusion: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Published
2016
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8. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, 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, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller 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, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, 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, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, 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, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, 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 M, 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, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, 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, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract

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 similar to 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.

Published
2014

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