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Search: onr:"swepub:oai:lup.lub.lu.se:d6e1c590-8d73-413d-980e-0fa453c577f5" > Discovery of Geneti...

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  • Smith, GustavLund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Institutionen för kliniska vetenskaper, Malmö,Heart Failure and Mechanical Support,Forskargrupper vid Lunds universitet,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Department of Clinical Sciences, Malmö,Lund University Research Groups,Massachusetts General Hospital,Broad Institute (author)

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • 2016-05-05
  • Public Library of Science (PLoS),2016

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:d6e1c590-8d73-413d-980e-0fa453c577f5
  • https://lup.lub.lu.se/record/d6e1c590-8d73-413d-980e-0fa453c577f5URI
  • https://doi.org/10.1371/journal.pgen.1006034DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Failure 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.

Subject headings and genre

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  • Felix, Janine F.Erasmus University Medical Center (author)
  • Morrison, Alanna C.University of Texas (author)
  • Kalogeropoulos, AndreasEmory Clinic (author)
  • Trompet, StellaLeiden University Medical Centre (author)
  • Wilk, Jemma B.Brigham and Women's Hospital / Harvard Medical School (author)
  • Gidlöf, OlofLund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-ogf (author)
  • Wang, XinchenMassachusetts Institute of Technology (author)
  • Morley, MichaelUniversity of Pennsylvania (author)
  • Mendelson, MichaelBoston Children's Hospital (author)
  • Joehanes, RobyNational Heart Lung and Blood Institute (author)
  • Ligthart, SymenErasmus University Medical Center (author)
  • Shan, XiaoyinUniversity of Pennsylvania (author)
  • Bis, Joshua C.University of Washington (author)
  • Wang, Ying A.Novartis Institutes for BioMedical Research, Inc. (author)
  • Sjögren, MarketaLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine(Swepub:lu)endo-msj (author)
  • Ngwa, JuliusBoston University (author)
  • Brandimarto, JeffreyUniversity of Pennsylvania (author)
  • Stott, David J.University of Glasgow (author)
  • Aguilar, DavidBaylor College of Medicine (author)
  • Rice, Kenneth M.University of Washington (author)
  • Sesso, Howard D.Brigham and Women's Hospital / Harvard Medical School (author)
  • Demissie, SerkalemBoston University (author)
  • Buckley, Brendan M.University College Cork (author)
  • Taylor, Kent D.University of California, Los Angeles (author)
  • Ford, IanUniversity of Glasgow (author)
  • Yao, ChenNational Heart Lung and Blood Institute (author)
  • Liu, ChunyuNational Heart Lung and Blood Institute (author)
  • Sotoodehnia, NonaUniversity of Washington (author)
  • van der Harst, PimUniversity of Groningen (author)
  • Stricker, Bruno H ChErasmus University Medical Center (author)
  • Kritchevsky, Stephen B.Wake Forest University (author)
  • Liu, YongmeiWake Forest University (author)
  • Gaziano, J. MichaelBrigham and Women's Hospital / Harvard Medical School (author)
  • Hofman, AlbertErasmus University Medical Center (author)
  • Moravec, Christine S.Cleveland Clinic Foundation (author)
  • Uitterlinden, André G.Erasmus University Medical Center (author)
  • Kellis, ManolisMassachusetts Institute of Technology (author)
  • van Meurs, Joyce B.Erasmus University Medical Center (author)
  • Margulies, Kenneth B.University of Pennsylvania (author)
  • Dehghan, AbbasErasmus University Medical Center (author)
  • Levy, DanielNational Heart Lung and Blood Institute (author)
  • Olde, BjörnLund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)mphy-bol (author)
  • Psaty, Bruce M.Kaiser Permanente Research Institute (author)
  • Cupples, L. AdrienneBoston University (author)
  • Jukema, J. WouterInteruniversity Cardiology Institute of the Netherlands (author)
  • Djousse, LucBrigham and Women's Hospital / Harvard Medical School (author)
  • Franco, Oscar H.Erasmus University Medical Center (author)
  • Boerwinkle, EricBaylor College of Medicine (author)
  • Boyer, Laurie A.Massachusetts Institute of Technology (author)
  • Newton-Cheh, ChristopherMassachusetts General Hospital (author)
  • Butler, JavedEmory Clinic (author)
  • Vasan, Ramachandran S.Boston University (author)
  • Cappola, Thomas P.University of Pennsylvania (author)
  • Smith, Nicholas L.Veterans Health Administration Office of Research and Development (author)
  • KardiologiSektion II (creator_code:org_t)

Related titles

  • In:PLoS Genetics: Public Library of Science (PLoS)12:51553-73901553-7404

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