Functional Annotation of Genetic Loci Associated With Sepsis Prioritizes Immune and Endothelial Cell Pathways.
Cells, Cultured
Endothelial Cells
/ immunology
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
/ methods
Humans
Leukocytes, Mononuclear
/ metabolism
Polymorphism, Single Nucleotide
Protein-Tyrosine Kinases
/ genetics
Quantitative Trait Loci
/ genetics
Sepsis
/ genetics
Signal Transduction
/ genetics
THP-1 Cells
Transcriptome
/ genetics
alpha-Mannosidase
/ genetics
FER locus
PBMC transcriptome
cytokine QTLs
eQTL
endothelial response
functional genomics
sepsis GWAS
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2019
2019
Historique:
received:
14
05
2019
accepted:
01
08
2019
entrez:
3
9
2019
pubmed:
3
9
2019
medline:
6
10
2020
Statut:
epublish
Résumé
Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants. By integrating expression quantitative trait loci (eQTL) results from the largest whole-blood eQTL database, cytokine QTLs from pathogen-stimulated peripheral blood mononuclear cells (PBMCs), publicly available blood transcriptome data from pneumoniae-derived sepsis patients, and transcriptome data from pathogen-stimulated PBMCs, we identified 55 potential genes affected by 39 independent loci. By performing pathway enrichment analysis at these loci we found enrichment of genes for adherences-junction pathway. Finally, we investigated the functional role of the only one GWAS significant SNP rs4957796 on sepsis survival in altering transcription factor binding affinity in monocytes and endothelial cells. We also found that transient deficiency of
Identifiants
pubmed: 31475010
doi: 10.3389/fimmu.2019.01949
pmc: PMC6703137
doi:
Substances chimiques
proto-oncogene protein c-fes-fps
110736-90-8
Protein-Tyrosine Kinases
EC 2.7.10.1
alpha-Mannosidase
EC 3.2.1.24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1949Références
Biochim Biophys Acta. 2002 Nov 20;1588(2):139-48
pubmed: 12385778
Genome Biol. 2008;9(12):R170
pubmed: 19061490
Int J Tuberc Lung Dis. 2009 Sep;13(9):1068-76
pubmed: 19723394
PLoS One. 2011 Jan 25;6(1):e15831
pubmed: 21283567
Front Biosci (Elite Ed). 2013 Jan 01;5:87-96
pubmed: 23276972
Genome Res. 2013 May;23(5):800-11
pubmed: 23512712
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):373-8
pubmed: 24344308
Lancet Respir Med. 2015 Jan;3(1):53-60
pubmed: 25533491
Anaesthesiol Intensive Ther. 2015;47 Spec No:s44-55
pubmed: 26578400
Epigenetics Chromatin. 2015 Dec 30;8:57
pubmed: 26719772
PLoS Comput Biol. 2016 Jan 25;12(1):e1004714
pubmed: 26808494
JAMA. 2016 Feb 23;315(8):801-10
pubmed: 26903338
Lancet Respir Med. 2016 Apr;4(4):259-71
pubmed: 26917434
J Immunol. 2016 Jun 1;196(11):4681-91
pubmed: 27183587
Nat Med. 2016 Aug;22(8):952-60
pubmed: 27376574
EBioMedicine. 2016 Oct;12:239-246
pubmed: 27639821
Cell. 2016 Nov 3;167(4):1099-1110.e14
pubmed: 27814507
Arch Dis Child Fetal Neonatal Ed. 2017 Sep;102(5):F439-F445
pubmed: 28283553
Nat Rev Immunol. 2017 Jul;17(7):407-420
pubmed: 28436424
PLoS One. 2017 Jul 20;12(7):e0180824
pubmed: 28727728
Lancet Respir Med. 2018 Mar;6(3):223-230
pubmed: 29508706
Front Immunol. 2018 Mar 16;9:483
pubmed: 29616022
Am J Hum Genet. 2018 May 3;102(5):717-730
pubmed: 29727686
N Engl J Med. 1998 Mar 5;338(10):640-4
pubmed: 9486992