Advanced

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

Smith, Gustav LU ; Felix, Janine F.; Morrison, Alanna C.; Kalogeropoulos, Andreas; Trompet, Stella; Wilk, Jemma B.; Gidlöf, Olof LU ; Wang, Xinchen; Morley, Michael and Mendelson, Michael, et al. (2016) In PLoS Genetics 12(5).
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
12
issue
5
publisher
Public Library of Science
external identifiers
  • Scopus:84974530805
ISSN
1553-7390
DOI
10.1371/journal.pgen.1006034
language
English
LU publication?
yes
id
d6e1c590-8d73-413d-980e-0fa453c577f5
date added to LUP
2016-07-07 13:43:42
date last changed
2016-11-06 04:38:59
@misc{d6e1c590-8d73-413d-980e-0fa453c577f5,
  abstract     = {<p>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<sup>-9</sup>). 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<sup>-40</sup>) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10<sup>-4</sup>). 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.</p>},
  author       = {Smith, Gustav and Felix, Janine F. and Morrison, Alanna C. and Kalogeropoulos, Andreas and Trompet, Stella and Wilk, Jemma B. and Gidlöf, Olof and Wang, Xinchen and Morley, Michael and Mendelson, Michael and Joehanes, Roby and Ligthart, Symen and Shan, Xiaoyin and Bis, Joshua C. and Wang, Ying A. and Sjögren, Marketa and Ngwa, Julius and Brandimarto, Jeffrey and Stott, David J. and Aguilar, David and Rice, Kenneth M. and Sesso, Howard D. and Demissie, Serkalem and Buckley, Brendan M. and Taylor, Kent D. and Ford, Ian and Yao, Chen and Liu, Chunyu and Sotoodehnia, Nona and van der Harst, Pim and Stricker, Bruno H Ch and Kritchevsky, Stephen B. and Liu, Yongmei and Gaziano, J. Michael and Hofman, Albert and Moravec, Christine S. and Uitterlinden, André G. and Kellis, Manolis and van Meurs, Joyce B. and Margulies, Kenneth B. and Dehghan, Abbas and Levy, Daniel and Olde, Björn and Psaty, Bruce M. and Cupples, L. Adrienne and Jukema, J. Wouter and Djousse, Luc and Franco, Oscar H. and Boerwinkle, Eric and Boyer, Laurie A. and Newton-Cheh, Christopher and Butler, Javed and Vasan, Ramachandran S. and Cappola, Thomas P. and Smith, Nicholas L.},
  issn         = {1553-7390},
  language     = {eng},
  month        = {05},
  number       = {5},
  publisher    = {ARRAY(0x989e930)},
  series       = {PLoS Genetics},
  title        = {Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1006034},
  volume       = {12},
  year         = {2016},
}