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Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples.

Authors
  • Rashidi, Armin1
  • Shanley, Ryan2
  • Yohe, Sophia L3
  • Thyagarajan, Bharat3
  • Curtsinger, Julie4
  • Anasetti, Claudio5
  • Waller, Edmund K6
  • Scott, Bart L7
  • Blazar, Bruce R8
  • Weisdorf, Daniel J1
  • 1 Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
  • 2 Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, MN, USA.
  • 3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
  • 4 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 5 Moffitt Cancer Center, Tampa, FL, USA.
  • 6 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
  • 7 Fred Hutchinson Cancer Research Center, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA, USA.
  • 8 Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Type
Published Article
Journal
British Journal of Haematology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Sep 01, 2018
Volume
182
Issue
6
Pages
887–894
Identifiers
DOI: 10.1111/bjh.15492
PMID: 30004111
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN-0201 and a SNP × conditioning intensity term in CTN-0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II-IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37-0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01-2·32, P = 0·05] in CTN-0201, but not CTN-0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function. © 2018 British Society for Haematology and John Wiley & Sons Ltd.

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