Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study.
Journal
The Lancet. Respiratory medicine
ISSN: 2213-2619
Titre abrégé: Lancet Respir Med
Pays: England
ID NLM: 101605555
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
26
04
2019
revised:
25
07
2019
accepted:
07
08
2019
pubmed:
27
1
2020
medline:
2
10
2020
entrez:
27
1
2020
Statut:
ppublish
Résumé
Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation. We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants. We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 × 10 A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target. Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
Sections du résumé
BACKGROUND
Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.
METHODS
We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.
FINDINGS
We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 × 10
INTERPRETATION
A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.
FUNDING
Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
Identifiants
pubmed: 31982041
pii: S2213-2600(19)30368-6
doi: 10.1016/S2213-2600(19)30368-6
pmc: PMC7772505
mid: NIHMS1650921
pii:
doi:
Substances chimiques
Vascular Endothelial Growth Factor A
0
FLT1 protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-1
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
258-266Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL130796
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137006
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137915
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Références
Nat Genet. 2013 Jan;45(1):25-33
pubmed: 23202125
Am J Respir Crit Care Med. 2018 Jun 1;197(11):1421-1432
pubmed: 29425463
Respirology. 2018 Oct;23(10):942-949
pubmed: 29741298
Mol Biol Evol. 2018 Dec 1;35(12):3010-3026
pubmed: 30289472
J Hum Genet. 2016 Oct;61(10):861-866
pubmed: 27305981
Cell. 2016 Nov 17;167(5):1415-1429.e19
pubmed: 27863252
N Engl J Med. 2014 May 29;370(22):2071-82
pubmed: 24836310
Trends Cardiovasc Med. 2003 Jul;13(5):169-75
pubmed: 12837578
Nat Genet. 2017 Aug;49(8):1255-1260
pubmed: 28628106
Crit Care Med. 2016 May;44(5):954-65
pubmed: 26807686
Am J Hum Genet. 2012 Aug 10;91(2):224-37
pubmed: 22863193
Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082
pubmed: 29126136
Am J Physiol Lung Cell Mol Physiol. 2001 Dec;281(6):L1500-11
pubmed: 11704547
N Engl J Med. 2000 May 4;342(18):1301-8
pubmed: 10793162
N Engl J Med. 2013 Jun 6;368(23):2159-68
pubmed: 23688302
J Allergy Clin Immunol. 2016 Mar;137(3):964-6
pubmed: 26620591
Shock. 2013 May;39(5):427-32
pubmed: 23524845
JAMA. 2016 Feb 23;315(8):801-10
pubmed: 26903338
PLoS One. 2014 Nov 05;9(11):e111953
pubmed: 25372662
Intensive Care Med. 2018 Nov;44(11):1849-1858
pubmed: 30343317
JAMA. 2016 Feb 23;315(8):788-800
pubmed: 26903337
Am J Respir Crit Care Med. 2010 May 15;181(10):1121-7
pubmed: 20224063
PLoS One. 2012;7(1):e28268
pubmed: 22295056
Ann Thorac Surg. 2012 Oct;94(4):1079-84; discussion 1084-5
pubmed: 22795057
Chest. 2017 Jul;152(1):22-31
pubmed: 28109962
Nat Genet. 2015 Jun;47(6):598-606
pubmed: 25938943
Bioinformatics. 2018 May 1;34(9):1498-1505
pubmed: 29236977
EBioMedicine. 2016 Oct;12:239-246
pubmed: 27639821
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9
pubmed: 8248162
J Biol Chem. 2011 Dec 23;286(51):44045-56
pubmed: 22025615
Eur Respir J. 2005 Jul;26(1):101-5
pubmed: 15994395
Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24
pubmed: 7509706
J Trauma Acute Care Surg. 2017 Apr;82(4):766-770
pubmed: 28099389
JAMA. 2012 Jun 20;307(23):2526-33
pubmed: 22797452
Respiration. 2014;87(4):329-42
pubmed: 24356493
Am J Obstet Gynecol. 2018 Feb;218(2):211-218
pubmed: 29138037
Crit Care. 2010;14(5):R182
pubmed: 20942957
Glob Heart. 2014 Sep;9(3):289-95
pubmed: 25667180
Intensive Care Med. 2011 Dec;37(12):1932-41
pubmed: 21997128