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Discovery of Geneti...
Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
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- Smith, Gustav (author)
- Lund 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
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- Felix, Janine F. (author)
- Erasmus University Medical Center
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- Morrison, Alanna C. (author)
- University of Texas
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- Kalogeropoulos, Andreas (author)
- Emory Clinic
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- Trompet, Stella (author)
- Leiden University Medical Centre
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- Wilk, Jemma B. (author)
- Brigham and Women's Hospital / Harvard Medical School
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- Gidlöf, Olof (author)
- Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Wang, Xinchen (author)
- Massachusetts Institute of Technology
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- Morley, Michael (author)
- University of Pennsylvania
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- Mendelson, Michael (author)
- Boston Children's Hospital
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- Joehanes, Roby (author)
- National Heart Lung and Blood Institute
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- Ligthart, Symen (author)
- Erasmus University Medical Center
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- Shan, Xiaoyin (author)
- University of Pennsylvania
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- Bis, Joshua C. (author)
- University of Washington
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- Wang, Ying A. (author)
- Novartis Institutes for BioMedical Research, Inc.
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- Sjögren, Marketa (author)
- Lund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine
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- Ngwa, Julius (author)
- Boston University
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- Brandimarto, Jeffrey (author)
- University of Pennsylvania
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- Stott, David J. (author)
- University of Glasgow
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- Aguilar, David (author)
- Baylor College of Medicine
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- Rice, Kenneth M. (author)
- University of Washington
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- Sesso, Howard D. (author)
- Brigham and Women's Hospital / Harvard Medical School
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- Demissie, Serkalem (author)
- Boston University
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- Buckley, Brendan M. (author)
- University College Cork
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- Taylor, Kent D. (author)
- University of California, Los Angeles
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- Ford, Ian (author)
- University of Glasgow
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- Yao, Chen (author)
- National Heart Lung and Blood Institute
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- Liu, Chunyu (author)
- National Heart Lung and Blood Institute
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- Sotoodehnia, Nona (author)
- University of Washington
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- van der Harst, Pim (author)
- University of Groningen
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- Stricker, Bruno H Ch (author)
- Erasmus University Medical Center
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- Kritchevsky, Stephen B. (author)
- Wake Forest University
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- Liu, Yongmei (author)
- Wake Forest University
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- Gaziano, J. Michael (author)
- Brigham and Women's Hospital / Harvard Medical School
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- Hofman, Albert (author)
- Erasmus University Medical Center
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- Moravec, Christine S. (author)
- Cleveland Clinic Foundation
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- Uitterlinden, André G. (author)
- Erasmus University Medical Center
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- Kellis, Manolis (author)
- Massachusetts Institute of Technology
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- van Meurs, Joyce B. (author)
- Erasmus University Medical Center
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- Margulies, Kenneth B. (author)
- University of Pennsylvania
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- Dehghan, Abbas (author)
- Erasmus University Medical Center
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- Levy, Daniel (author)
- National Heart Lung and Blood Institute
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- Olde, Björn (author)
- Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Psaty, Bruce M. (author)
- Kaiser Permanente Research Institute
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- Cupples, L. Adrienne (author)
- Boston University
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- Jukema, J. Wouter (author)
- Interuniversity Cardiology Institute of the Netherlands
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- Djousse, Luc (author)
- Brigham and Women's Hospital / Harvard Medical School
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- Franco, Oscar H. (author)
- Erasmus University Medical Center
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- Boerwinkle, Eric (author)
- Baylor College of Medicine
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- Boyer, Laurie A. (author)
- Massachusetts Institute of Technology
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- Newton-Cheh, Christopher (author)
- Massachusetts General Hospital
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- Butler, Javed (author)
- Emory Clinic
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- Vasan, Ramachandran S. (author)
- Boston University
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- Cappola, Thomas P. (author)
- University of Pennsylvania
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- Smith, Nicholas L. (author)
- Veterans Health Administration Office of Research and Development
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(creator_code:org_t)
- 2016-05-05
- 2016
- English.
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
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Abstract
Subject headings
Close
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Smith, Gustav
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Felix, Janine F.
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Morrison, Alanna ...
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Kalogeropoulos, ...
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Trompet, Stella
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Wilk, Jemma B.
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show more...
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Gidlöf, Olof
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Wang, Xinchen
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Morley, Michael
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Mendelson, Micha ...
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Joehanes, Roby
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Ligthart, Symen
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Shan, Xiaoyin
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Bis, Joshua C.
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Wang, Ying A.
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Sjögren, Marketa
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Ngwa, Julius
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Brandimarto, Jef ...
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Stott, David J.
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Aguilar, David
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Rice, Kenneth M.
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Sesso, Howard D.
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Demissie, Serkal ...
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Buckley, Brendan ...
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Taylor, Kent D.
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Ford, Ian
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Yao, Chen
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Liu, Chunyu
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Sotoodehnia, Non ...
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van der Harst, P ...
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Stricker, Bruno ...
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Kritchevsky, Ste ...
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Liu, Yongmei
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Gaziano, J. Mich ...
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Hofman, Albert
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Moravec, Christi ...
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Uitterlinden, An ...
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Kellis, Manolis
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van Meurs, Joyce ...
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Margulies, Kenne ...
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Dehghan, Abbas
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Levy, Daniel
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Olde, Björn
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Psaty, Bruce M.
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Cupples, L. Adri ...
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Jukema, J. Woute ...
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Djousse, Luc
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Franco, Oscar H.
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Boerwinkle, Eric
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Boyer, Laurie A.
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Newton-Cheh, Chr ...
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Butler, Javed
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Vasan, Ramachand ...
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Cappola, Thomas ...
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Smith, Nicholas ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
- Articles in the publication
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PLoS Genetics
- By the university
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Lund University