Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection.
RNA sequencing
T cell–mediated rejection
antibody-mediated rejection
kidney transplantation
systems biology
Journal
Kidney international reports
ISSN: 2468-0249
Titre abrégé: Kidney Int Rep
Pays: United States
ID NLM: 101684752
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
01
04
2020
revised:
19
06
2020
accepted:
21
07
2020
entrez:
26
10
2020
pubmed:
27
10
2020
medline:
27
10
2020
Statut:
epublish
Résumé
Peripheral blood (PB) molecular patterns characterizing the different effector immune pathways driving distinct kidney rejection types remain to be fully elucidated. We hypothesized that transcriptome analysis using RNA sequencing (RNAseq) in samples of kidney transplant patients would enable the identification of unique protein-coding and noncoding genes that may be able to segregate different rejection phenotypes. We evaluated 37 biopsy-paired PB samples from the discovery cohort, with stable (STA), antibody-mediated rejection (AMR), and T cell-mediated rejection (TCMR) by RNAseq. Advanced machine learning tools were used to perform 3-way differential gene expression analysis to identify gene signatures associated with rejection. We then performed functional in silico analysis and validation by Fluidigm (San Francisco, CA) in 62 samples from 2 independent kidney transplant cohorts. We found 102 genes (63 coding genes and 39 noncoding genes) associated with AMR (54 upregulated), TCMR (23 upregulated), and STA (25 upregulated) perfectly clustered with each rejection phenotype and highly correlated with main histologic lesions (ρ = 0.91). For the genes associated with AMR, we found enrichment in regulation of endoplasmic reticulum stress, adaptive immunity, and Ig class-switching. In the validation, we found that the This analysis identifies a critical gene signature in PB in kidney transplant patients undergoing AMR, sufficient to differentiate them from patients with TCMR and immunologically quiescent kidney allografts. Our findings provide the basis for new studies dissecting the role of noncoding genes in the pathophysiology of kidney allograft rejection and their potential value as noninvasive biomarkers of the rejection process.
Identifiants
pubmed: 33102963
doi: 10.1016/j.ekir.2020.07.023
pii: S2468-0249(20)31422-4
pmc: PMC7569686
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1706-1721Subventions
Organisme : NIAID NIH HHS
ID : U19 AI128913
Pays : United States
Informations de copyright
© 2020 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.
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