Discovery of genetic variation on chromosome 5q22 associated with mortality in heart failure

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dc.contributor.authorSmith, J. Gustav
dc.contributor.authorFelix, Janine F.
dc.contributor.authorMorrison, Alanna C.
dc.contributor.authorKalogeropoulos, Andreas
dc.contributor.authorTrompet, Stella
dc.contributor.authorWilk, Jemma B.
dc.contributor.authorGidlöf, Olof
dc.contributor.authorWang, Xinchen
dc.contributor.authorMorley, Michael
dc.contributor.authorMendelson, Michael
dc.contributor.authorJoehanes, Roby
dc.contributor.authorLigthart, Symen
dc.contributor.authorShan, Xiaoyin
dc.contributor.authorBis, Joshua C.
dc.contributor.authorWang, Ying A.
dc.contributor.authorSjögren, Marketa
dc.contributor.authorNgwa, Julius
dc.contributor.authorBrandimarto, Jeffrey
dc.contributor.authorStott, David J.
dc.contributor.authorAguilar, David
dc.contributor.authorRice, Kenneth M.
dc.contributor.authorSesso, Howard D.
dc.contributor.authorDemissie, Serkalem
dc.contributor.authorBuckley, Brendan M.
dc.contributor.authorTaylor, Kent D.
dc.contributor.authorFord, Ian
dc.contributor.authorYao, Chen
dc.contributor.authorLiu, Chunyu
dc.contributor.authorCHARGE-SCD consortium
dc.contributor.authorEchoGen, consortium
dc.contributor.authorQT-IGC consortium
dc.contributor.authorCHARGE-QRS consortium
dc.contributor.authorSotoodehnia, Nona
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorStricker, Bruno H. Ch
dc.contributor.authorKritchevsky, Stephen B.
dc.contributor.authorLiu, Yongmei
dc.contributor.authorGaziano, J. Michael
dc.contributor.authorHofman, Albert
dc.contributor.authorMoravec, Christine S.
dc.contributor.authorUitterlinden, André G.
dc.contributor.authorKellis, Manolis
dc.contributor.authorvan Meurs, Joyce B.
dc.contributor.authorMargulies, Kenneth B.
dc.contributor.authorDehghan, Abbas
dc.contributor.authorLevy, Daniel
dc.contributor.authorOlde, Björn
dc.contributor.authorPsaty, Bruce M.
dc.contributor.authorCupples, L. Adrienne
dc.contributor.authorJukema, J. Wouter
dc.contributor.authorDjousse, Luc
dc.contributor.authorFranco, Oscar H.
dc.contributor.authorBoerwinkle, Eric
dc.contributor.authorBoyer, Laurie A.
dc.contributor.authorNewton-Cheh, Christopher
dc.contributor.authorButler, Javed
dc.contributor.authorVasan, Ramachandran S.
dc.contributor.authorCappola, Thomas P.
dc.contributor.authorSmith, Nicholas L.
dc.contributor.funderNational Heart, Lung, and Blood Institute
dc.contributor.funderNational Human Genome Research Institute
dc.contributor.funderNational Institutes of Health
dc.contributor.funderNational Institute of Environmental Health Sciences
dc.contributor.funderBristol-Myers Squibb Foundation
dc.contributor.funderNational Institute on Aging
dc.contributor.funderNational Institute of Diabetes and Digestive and Kidney Diseases
dc.contributor.funderSeventh Framework Programme
dc.contributor.funderHartstichting
dc.contributor.funderNetherlands Genomics Initiative
dc.contributor.funderNederlandse Organisatie voor Wetenschappelijk Onderzoek
dc.contributor.funderResearch Institute for Diseases in the Elderly
dc.contributor.funderErasmus Medisch Centrum
dc.contributor.funderErasmus Universiteit Rotterdam
dc.contributor.funderZonMw
dc.contributor.funderMinisterie van Onderwijs, Cultuur en Wetenschap
dc.contributor.funderMinisterie van Volksgezondheid, Welzijn en Sport
dc.contributor.funderEuropean Commission
dc.contributor.funderMunicipality of Rotterdam
dc.contributor.funderFondation Nestlé
dc.contributor.funderMetagenics Inc.
dc.contributor.funderAXA Research Fund
dc.contributor.funderCancerfonden
dc.contributor.funderMedicinska Forskningsrådet
dc.contributor.funderSwedish Dairy Association
dc.contributor.funderDirektör Albert Påhlssons Stiftelse
dc.contributor.funderGunnar Nilssons Cancerstiftelse
dc.contributor.funderMalmö City Council
dc.contributor.funderPublic Health Agency of Sweden
dc.contributor.funderMärta Winkler Foundation
dc.contributor.funderHjärt-Lungfonden
dc.contributor.funderSwedish Society of Cardiology
dc.contributor.funderVetenskapsrådet
dc.contributor.funderEuropean Research Council
dc.contributor.funderSkåne University Hospital
dc.contributor.funderCrafoordska Stiftelsen
dc.contributor.funderNational Cancer Institute
dc.date.accessioned2017-06-21T11:01:26Z
dc.date.available2017-06-21T11:01:26Z
dc.date.issued2016-05-05
dc.description.abstractFailure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.en
dc.description.sponsorshipNational Heart, Lung, and Blood Institute (Contracts (HHSN268201100005C; HHSN268201100006C; HHSN268201100007C; HHSN268201100008C; HHSN268201100009C; HHSN268201100010C; HHSN268201100011C; and HHSN268201100012C; N01-HC-55015; N01-HC-55016; N01-HC-55018; N01-HC-55019; N01-HC-55020; N01-HC-55021; N01-HC-55022; R01HL087641; R01HL59367; R01HL086694; HHSN268201200036C; HHSN268200800007C; N01HC55222; N01HC85079; N01HC85080; N01HC85081; N01HC85082; N01HC85083; N01HC85086; U01HL080295; R01HL087652; R01HL105756; R01HL103612; R01HL120393; N01-HC-25195; N02-HL-6-4278; 2K24HL04334; R01HL077477; R01HL093328; R01HL105993; HL-26490; HL-34595; SHARe Project); National Human Genome Research Institute (Contract U01HG004402); National Institutes of Health (Contracts HHSN268200625226C; HHSN268200782096C) National Institutes of Health and NIH Roadmap for Medical Research (Grant Number UL1RR025005); NIH and National Institute of Environmental Health Sciences (Intramural research program); National Institute on Aging (R01AG023629; N01AG62101; N01AG62103; N01AG62106; 1R01AG032098-01A1; Intramural Research Program); National Center for Advancing Translational Sciences (CTSI grant UL1TR000124); National Institute of Diabetes and Digestive and Kidney Disease (Diabetes Research Center Grant DK063491 to the Southern California Diabetes Endocrinology Research Center); Nederlandse Hartstichting (Grant 2001 D 032); Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810); Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Investment Nos. 175.010.2005.011 and 911-03-012;); Research Institute for Diseases in the Elderly (014-93-015; RIDE2); National Cancer Institute (Grants CA-34944; CA-40360; CA-097193)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide1006034
dc.identifier.citationSmith, J. G., Felix, J. F., Morrison, A. C., Kalogeropoulos, A., Trompet, S., Wilk, J. B., Gidlöf, O., Wang, X., Morley, M., Mendelson, M., Joehanes, R., Ligthart, S., Shan, X., Bis, J. C., Wang, Y. A., Sjögren, M., Ngwa, J., Brandimarto, J., Stott, D. J., Aguilar, D., Rice, K. M., Sesso, H. D., Demissie, S., Buckley, B. M., Taylor, K. D., Ford, I., Yao, C., Liu, C., CHARGE-SCD consortium , EchoGen consortium , QT-IGC consortium , CHARGE-QRS consortium, Sotoodehnia, N., van der Harst, P., Stricker, B. H. C., Kritchevsky, S. B., Liu, Y., Gaziano, J. M., Hofman, A., Moravec, C. S., Uitterlinden, A. G., Kellis, M., van Meurs, J. B., Margulies, K. B., Dehghan, A., Levy, D., Olde, B., Psaty, B. M., Cupples, L. A., Jukema, J. W., Djousse, L., Franco, O. H., Boerwinkle, E., Boyer, L. A., Newton-Cheh, C., Butler, J., Vasan, R. S., Cappola, T. P. and Smith, N. L. (2016) 'Discovery of genetic variation on chromosome 5q22 associated with mortality in heart failure', PLoS Genetics, 12(5), e1006034 (19pp). doi: 10.1371/journal.pgen.1006034en
dc.identifier.doi10.1371/journal.pgen.1006034
dc.identifier.endpage19
dc.identifier.issn1553-7390
dc.identifier.issn1553-7404
dc.identifier.issued5
dc.identifier.journaltitlePLoS Geneticsen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/4136
dc.identifier.volume12
dc.language.isoenen
dc.publisherPLoSen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/223004/EU/A PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease/PHASE
dc.relation.urihttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006034
dc.rights© 2016, Smith et al. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.en
dc.rights.urihttps://creativecommons.org/publicdomain/zero/1.0/en
dc.subjectHeart failureen
dc.subjectDNA methylationen
dc.subjectGene expressionen
dc.subjectDeath ratesen
dc.subjectGenome-wide association studiesen
dc.subjectGenetic locien
dc.subjectBlooden
dc.subjectChromosomesen
dc.titleDiscovery of genetic variation on chromosome 5q22 associated with mortality in heart failureen
dc.typeArticle (peer-reviewed)en
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