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

• Type of Material: Article
• Authors: Armin Rashidi, University of Minnesota; Ryan Shanley, University of Minnesota; Sophia L. Yohe, University of Minnesota; Bharat Thyagarajan, University of Minnesota; Julie Curtsinger, University of Minnesota; Claudio Anasetti, Moffitt Cancer Center; Edmund K Waller, Emory University; Bart L. Scott, University of Washington; Bruce R. Blazar, University of Minnesota; Daniel J. Weisdorf, University of Minnesota
• Language: English
• Date: 2018-09-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 British Society for Haematology and John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/bjh.15492
• Title of Journal or Parent Work: British Journal of Haematology
• ISSN: 0007-1048
• Volume: 182
• Issue: 6
• Start Page: 887
• End Page: 894
• Grant/Funding Information: Research reported in this publication was also supported by NIH grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114.; Armin Rashidi was supported by an American Blood and Marrow Transplantation Young Investigator Award.; Support for this study was provided to the Blood and Marrow Transplant Clinical Trials Network by grant #U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute.; Enrolment support was provided by DKMS Germany.
• Keywords: MARROW TRANSPLANT; BLOOD; LECTIN REGIII-GAMMA; ANTIBIOTICS; RISK; GUT MICROBIOME; Life Sciences & Biomedicine; Hematology; EXPRESSION; SNP; defensin; Science & Technology; microbiota; METABOLITES; GVHD; ALPHA-DEFENSINS; BACTERICIDAL LECTIN; Reg3 alpha
• Research Categories: Health Sciences, Medicine and Surgery

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.