Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
(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)
- author
- organization
- publishing date
- 2016-05-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Genetics
- volume
- 12
- issue
- 5
- article number
- e1006034
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000377197100035
- pmid:27149122
- 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
- 2024-04-05 03:35:10
@article{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 = {{Public Library of Science (PLoS)}},
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}},
doi = {{10.1371/journal.pgen.1006034}},
volume = {{12}},
year = {{2016}},
}