Research Paper
Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples
Armin Rashidi,
Ryan Shanley,
Sophia L. Yohe,
Bharat Thyagarajan,
Julie Curtsinger,
Claudio Anasetti, Edmund K. Waller,
Bart L. Scott,
Bruce R. Blazar,
Daniel J. Weisdorf,
Corresponding Author
Armin Rashidi
Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
These authors contributed equally to this work.Correspondence: Armin Rashidi, Division of Hematology Oncology and Transplantation, Department of Medicine, University of Minnesota, 14-100 PWB, MMC480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
E-mail: [email protected]
Search for more papers by this authorRyan Shanley
Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, MN, USA
These authors contributed equally to this work.Search for more papers by this authorSophia L. Yohe
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorBharat Thyagarajan
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorJulie Curtsinger
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorEdmund K. Waller
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
Search for more papers by this authorBart L. Scott
Fred Hutchinson Cancer Research Center, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA, USA
Search for more papers by this authorBruce R. Blazar
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorDaniel J. Weisdorf
Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorArmin Rashidi,
Ryan Shanley,
Sophia L. Yohe,
Bharat Thyagarajan,
Julie Curtsinger,
Claudio Anasetti, Edmund K. Waller,
Bart L. Scott,
Bruce R. Blazar,
Daniel J. Weisdorf,
Corresponding Author
Armin Rashidi
Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
These authors contributed equally to this work.Correspondence: Armin Rashidi, Division of Hematology Oncology and Transplantation, Department of Medicine, University of Minnesota, 14-100 PWB, MMC480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
E-mail: [email protected]
Search for more papers by this authorRyan Shanley
Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, MN, USA
These authors contributed equally to this work.Search for more papers by this authorSophia L. Yohe
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorBharat Thyagarajan
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorJulie Curtsinger
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorEdmund K. Waller
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
Search for more papers by this authorBart L. Scott
Fred Hutchinson Cancer Research Center, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA, USA
Search for more papers by this authorBruce R. Blazar
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorDaniel J. Weisdorf
Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Search for more papers by this authorSummary
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.
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