title: A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.
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.
authors.affiliation: UCL Cancer Institute, University College London, London, UK. d.paul@ucl.ac.uk.
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.affiliation: UCL Cancer Institute, University College London, London, UK.|Department of Haematology, University College London, University College London Hospital, London, UK.
authors.forename: Rob S
authors.initials: RS
authors.lastname: Sellar
authors.affiliation: UCL Cancer Institute, University College London, London, UK.|Anthony Nolan Research Institute, Royal Free Hospital, London, UK.
authors.forename: Neema P
authors.initials: NP
authors.lastname: Mayor
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: UCL Cancer Institute, University College London, London, UK.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Webster
authors.affiliation: Department of Haematology, University College London, Royal Free Hospital, London, UK.
authors.forename: Neuza
authors.initials: N
authors.lastname: Afonso
authors.affiliation: Clinical Immunology, Imperial NHS Trust Hammersmith Hospital, London, UK.
authors.forename: Ruhena
authors.initials: R
authors.lastname: Sergeant
authors.affiliation: Centre for Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.|Department of Clinical Haematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Szydlo
authors.affiliation: Centre for Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.|Department of Clinical Haematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: UCL Cancer Institute, University College London, London, UK.|Department of Haematology, University College London, Royal Free Hospital, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mackinnon
authors.affiliation: UCL Cancer Institute, University College London, London, UK.|Anthony Nolan Research Institute, Royal Free Hospital, London, UK.
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
authors.affiliation: UCL Cancer Institute, University College London, London, UK.|Anthony Nolan Research Institute, Royal Free Hospital, London, UK.
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. v.rakyan@qmul.ac.uk.
authors.forename: Vardhman K
authors.initials: VK
authors.lastname: Rakyan
authors.affiliation: UCL Cancer Institute, University College London, London, UK. karl.peggs@ucl.ac.uk.|Department of Haematology, University College London, University College London Hospital, London, UK. karl.peggs@ucl.ac.uk.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Peggs
authors.affiliation: UCL Cancer Institute, University College London, London, UK. s.beck@ucl.ac.uk.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000009:adverse effects; D055815:Young Adult
chemical_list: D006680:HLA Antigens