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Smith, 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.S.* ; 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 (Butler, J.) ; EchoGen Consortium (Vasan, R.S. ; Cappola, T.P.) ; QT-IGC Consortium (Smith, N.L. ; Gieger, C. ; Perz, S. ; Peters, A. ; Pfeufer, A. ; Waldenberger, M. ; Crotti, L.) ; CHARGE-QRS Consortium (Klopp, N. ; Müller-Nurasyid, M. ; Perz, S. ; Wichmann, H.-E. ; Meitinger, T.) ; Sotoodehnia, N.* ; van der Harst, P.* ; Stricker, B.H.* ; 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.*

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

PLoS Genet. 12:e1006034 (2016)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Journal PLoS Genetics
Quellenangaben Volume: 12, Issue: 5, Pages: , Article Number: e1006034 Supplement: ,
Publisher Public Library of Science (PLoS)
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Biological and Medical Imaging (IBMI)
Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)