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Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies

Nolte, IM; Wallace, C; Newhouse, SJ; Waggott, D; Fu, JY; Soranzo, N; Gwilliam, R; ... QTSCD Consortium, ; + view all (2009) Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies. PLOS ONE , 4 (7) , Article e6138. 10.1371/journal.pone.0006138. Green open access


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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 < 1 x 10(-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 = 1.4 x 10-(83)) and the phospholamban (PLN) gene (P = 1.9 x 10(-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.

Type: Article
Title: Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0006138
Publisher version: http://dx.doi.org/10.1371/journal.pone.0006138
Language: English
Additional information: © 2009 Nolte et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For TwinsUK: This study was funded by the British Heart Foundation, Project grant No. 06/094. The study was also funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413 and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Dept of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. TDS is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant(G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI: Terri Young). CD is supported by a British Heart Foundation grant: SP/02/001. For the BRIGHT study: The BRIGHT study is supported by the Medical Research Council of Great Britain (grant number; G9521010D) and the British Heart Foundation (grant number PG02/128). CW was funded by the British Heart Foundation (grant number: FS/05/061/19501). SJN is funded by the Medical Research Council and The William Harvey Research Foundation. Profs Dominiczak and Samani are British Heart Foundation Chairholders. EZ is funded by the Wellcome Trust (WT088885/Z/09/Z). For the DCCT/EDIC study: The DCCT/EDIC Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health. The authors are grateful to the subjects in the DCCT/EDIC cohort for their long-term participation. A.D.P. holds a Canada Research Chair in the Genetics of Complex Diseases. This work has received support from National Institute of Diabetes and Digestive and Kidney Diseases Contract N01-DK-6-2204, National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-077510 and support from the Canadian Network of Centres of Excellence in Mathematics and Genome Canada through the Ontario Genomics Institute. For QTSCD: ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. In addition, we acknowledge support from NHLBI grants HL86694 and HL054512, and the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University for genotyping and data analysis relevant to this study. AK is supported by a German Research Foundation Fellowship. The KORA study was funded by the State of Bavaria and by grants from the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET) and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) by grants to Stefan Kaab (NGFN 01GS0499, 01GS0838 and AF-Net 01GI0204/N), Arne Pfeufer (NGFN 01GR0803, 01EZ0874), H. -Erich Wichmann (NGFN 01GI0204) and to Thomas Meitinger (NGFN 01GR0103). Stefan Kaab is also supported by a grant from the Fondation Leducq. The SardiNIA team was supported by Contract NO1-AG-1-2109 from the National Institute on Aging contract NO1-AG-1-2109 to the SardiNIA (“ProgeNIA”) team and in part by the Intramural Research Program of the US National Institute on Aging, NIH. The efforts of G.R.A. were supported in part by contract 263-MA-410953 from the National Institute on Aging to the University of Michigan and by research grants from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute (to G.R.A.). The GenNOVA study was supported by the Ministry of Health of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The Heinz Nixdorf Recall Study was funded by a grant of the Heinz Nixdorf Foundation (Chairman: Dr. jur. G. Schmidt). For QTGEN: The Framingham Heart Study work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and the Doris Duke Charitable Foundation (C.N.-C.) and Burroughs Wellcome Fund (C.N.-C.), based on analyses by Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. The measurement of ECG intervals in Framingham Heart Study generation 1 and 2 samples was performed by eResearchTechnology and was supported by an unrestricted grant from Pfizer. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (#175.010.2005.011, 911- 03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project #050-060-810. The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. C.N.-C. is supported by NIH K23-HL-080025, a Doris Duke Charitable Foundation Clinical Scientist Development Award, and a Burroughs Wellcome Fund Career Award for Medical Scientists. M.E is funded by the Netherlands Heart Foundation 2007B221. J.I.R. is supported by the Cedars-Sinai Board of Governors' Chair in Medical Genetics. The measurement of ECG intervals in the Framingham Heart Study generation 3 sample was completed by Alim Hirji and Sirisha Kovvali using AMPS software provided through an unrestricted academic license by AMPS, LLC (New York, NY,) USAA full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The authors acknowledge the essential role of the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium in development and support of this manuscript. CHARGE members include the Netherland's Rotterdam Study, the NHLBI's Atherosclerosis Risk in Communities (ARIC) Study, Cardiovascular Health Study (CHS) and Framingham Heart Study (FHS), and the NIA's Iceland Age, Gene/Environment Susceptibility (AGES) Study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
URI: http://discovery.ucl.ac.uk/id/eprint/1332675
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