Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BR...
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Public Library of Science (PLoS)
2009-07-01
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| author | Ilja M Nolte Chris Wallace Stephen J Newhouse Daryl Waggott Jingyuan Fu Nicole Soranzo Rhian Gwilliam Panos Deloukas Irina Savelieva Dongling Zheng Chrysoula Dalageorgou Martin Farrall Nilesh J Samani John Connell Morris Brown Anna Dominiczak Mark Lathrop Eleftheria Zeggini Louise V Wain Wellcome Trust Case Control Consortium DCCT/EDIC Research Group Christopher Newton-Cheh Mark Eijgelsheim Kenneth Rice Paul I W de Bakker QTGEN consortium Arne Pfeufer Serena Sanna Dan E Arking QTSCD consortium Folkert W Asselbergs Tim D Spector Nicholas D Carter Steve Jeffery Martin Tobin Mark Caulfield Harold Snieder Andrew D Paterson Patricia B Munroe Yalda Jamshidi |
| author_facet | Ilja M Nolte Chris Wallace Stephen J Newhouse Daryl Waggott Jingyuan Fu Nicole Soranzo Rhian Gwilliam Panos Deloukas Irina Savelieva Dongling Zheng Chrysoula Dalageorgou Martin Farrall Nilesh J Samani John Connell Morris Brown Anna Dominiczak Mark Lathrop Eleftheria Zeggini Louise V Wain Wellcome Trust Case Control Consortium DCCT/EDIC Research Group Christopher Newton-Cheh Mark Eijgelsheim Kenneth Rice Paul I W de Bakker QTGEN consortium Arne Pfeufer Serena Sanna Dan E Arking QTSCD consortium Folkert W Asselbergs Tim D Spector Nicholas D Carter Steve Jeffery Martin Tobin Mark Caulfield Harold Snieder Andrew D Paterson Patricia B Munroe Yalda Jamshidi |
| author_sort | Ilja M Nolte |
| collection | DOAJ |
| description | To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death. |
| format | Article |
| id | doaj-art-a075bafac4a04e268a97868576cece99 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2009-07-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-a075bafac4a04e268a97868576cece992025-08-20T03:22:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-07-0147e613810.1371/journal.pone.0006138Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.Ilja M NolteChris WallaceStephen J NewhouseDaryl WaggottJingyuan FuNicole SoranzoRhian GwilliamPanos DeloukasIrina SavelievaDongling ZhengChrysoula DalageorgouMartin FarrallNilesh J SamaniJohn ConnellMorris BrownAnna DominiczakMark LathropEleftheria ZegginiLouise V WainWellcome Trust Case Control ConsortiumDCCT/EDIC Research GroupChristopher Newton-ChehMark EijgelsheimKenneth RicePaul I W de BakkerQTGEN consortiumArne PfeuferSerena SannaDan E ArkingQTSCD consortiumFolkert W AsselbergsTim D SpectorNicholas D CarterSteve JefferyMartin TobinMark CaulfieldHarold SniederAndrew D PatersonPatricia B MunroeYalda JamshidiTo identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0006138&type=printable |
| spellingShingle | Ilja M Nolte Chris Wallace Stephen J Newhouse Daryl Waggott Jingyuan Fu Nicole Soranzo Rhian Gwilliam Panos Deloukas Irina Savelieva Dongling Zheng Chrysoula Dalageorgou Martin Farrall Nilesh J Samani John Connell Morris Brown Anna Dominiczak Mark Lathrop Eleftheria Zeggini Louise V Wain Wellcome Trust Case Control Consortium DCCT/EDIC Research Group Christopher Newton-Cheh Mark Eijgelsheim Kenneth Rice Paul I W de Bakker QTGEN consortium Arne Pfeufer Serena Sanna Dan E Arking QTSCD consortium Folkert W Asselbergs Tim D Spector Nicholas D Carter Steve Jeffery Martin Tobin Mark Caulfield Harold Snieder Andrew D Paterson Patricia B Munroe Yalda Jamshidi Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS ONE |
| title | Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. |
| title_full | Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. |
| title_fullStr | Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. |
| title_full_unstemmed | Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. |
| title_short | Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. |
| title_sort | common genetic variation near the phospholamban gene is associated with cardiac repolarisation meta analysis of three genome wide association studies |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0006138&type=printable |
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