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A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell

Title: A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell
Authors: Paul, DS
Jones, A
Sellar, RS
Mayor, NP
Feber, A
Webster, AP
Afonso, N
Sergeant, R
Szydlo, RM
Apperley, JF
Widschwendter, M
Mackinnon, S
Marsh, SGE
Madrigal, JA
Rakyan, VK
Peggs, KS
Beck, S
Item Type: Journal Article
Abstract: Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. Methods We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Results Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95 % CI = 0.96–0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Conclusions Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.
Issue Date: 15-Dec-2015
Date of Acceptance: 12-Nov-2015
URI: http://hdl.handle.net/10044/1/40899
DOI: http://dx.doi.org/10.1186/s13073-015-0246-z
ISSN: 1756-994X
Publisher: BioMed Central
Journal / Book Title: Genome Medicine
Volume: 7
Copyright Statement: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: National Institute for Health Research
Funder's Grant Number: NF-SI-0611-10275
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
EPIGENOME-WIDE ASSOCIATION
DNA METHYLATION
T-CELLS
SYSTEMATIC ANNOTATION
SHRUNKEN CENTROIDS
CANCER
BLOOD
EXPRESSION
BIOMARKERS
DISCOVERY
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Article Number: 128
Appears in Collections:Department of Medicine
Faculty of Medicine



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