TY - JOUR
T1 - Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
AU - Smith, J. Gustav
AU - Felix, Janine F.
AU - Morrison, Alanna C.
AU - Kalogeropoulos, Andreas
AU - Trompet, Stella
AU - Wilk, Jemma B.
AU - Gidlöf, Olof
AU - Wang, Xinchen
AU - Morley, Michael
AU - Mendelson, Michael
AU - Joehanes, Roby
AU - Ligthart, Symen
AU - Shan, Xiaoyin
AU - Bis, Joshua C.
AU - Wang, Ying A.
AU - Sjögren, Marketa
AU - Ngwa, Julius
AU - Brandimarto, Jeffrey
AU - Stott, David J.
AU - Aguilar, David
AU - Rice, Kenneth M.
AU - Sesso, Howard D.
AU - Demissie, Serkalem
AU - Buckley, Brendan M.
AU - Taylor, Kent D.
AU - Ford, Ian
AU - Yao, Chen
AU - Liu, Chunyu
AU - Sotoodehnia, Nona
AU - van der Harst, Pim
AU - Stricker, Bruno H.Ch
AU - Kritchevsky, Stephen B.
AU - Liu, Yongmei
AU - Gaziano, J. Michael
AU - Hofman, Albert
AU - Moravec, Christine S.
AU - Uitterlinden, André G.
AU - Kellis, Manolis
AU - van Meurs, Joyce B.
AU - Margulies, Kenneth B.
AU - Dehghan, Abbas
AU - Levy, Daniel
AU - Olde, Björn
AU - Psaty, Bruce M.
AU - Cupples, L. Adrienne
AU - Jukema, J. Wouter
AU - Djousse, Luc
AU - Franco, Oscar H.
AU - Boerwinkle, Eric
AU - Boyer, Laurie A.
N1 - Publisher Copyright:
© 2016 Public Library of Science. All Rights Reserved.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1006034
DO - 10.1371/journal.pgen.1006034
M3 - Article
C2 - 27149122
AN - SCOPUS:84974530805
SN - 1553-7390
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
IS - 5
M1 - e1006034
ER -