Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD.
Adolescent
Adult
Aged
Child
Child, Preschool
Cohort Studies
Cytokines
/ metabolism
Female
Gene Expression
Genome-Wide Association Study
Graft vs Host Disease
/ genetics
Hematopoietic Stem Cell Transplantation
/ adverse effects
Humans
Male
Middle Aged
Signal Transduction
/ genetics
T-Lymphocytes
/ immunology
Tissue Donors
Transplant Recipients
Transplantation, Homologous
/ adverse effects
Young Adult
GWAS
GvHD
HSCT
gene expression
meta-analysis
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
11
11
2019
accepted:
07
01
2020
entrez:
3
3
2020
pubmed:
3
3
2020
medline:
20
2
2021
Statut:
epublish
Résumé
Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR] <0.1). In support of our hypothesis, this number was significantly higher than that in a permutation meta-analysis involving the whole data set, as well as in separate meta-analyses on the GWAS and gene expression data sets. The genes indicated by the meta-analysis were significantly enriched in 277 Gene Ontology terms (FDR < 0.05), such as T cell function and cytokine-mediated signaling pathways, and the results highlighted several established immune mediators, such as interleukins and JAK-STAT signaling, and presented TRAF6 and TERT as potential effector candidates. Altogether, the results support the chosen methodological approach, implicate a role of gene-level variation in donors' key immunological regulators predisposing patients to acute GVHD, and present potential targets for therapeutic intervention.
Identifiants
pubmed: 32117222
doi: 10.3389/fimmu.2020.00019
pmc: PMC7008714
doi:
Substances chimiques
Cytokines
0
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19Informations de copyright
Copyright © 2020 Hyvärinen, Koskela, Niittyvuopio, Nihtinen, Volin, Salmenniemi, Putkonen, Buño, Gallardo, Itälä-Remes, Partanen and Ritari.
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