Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/cytokine The impact of cytokine gene polymorphisms on the outcome of HLA matched sibling hematopoietic stem cell transplantation Azza M. Kamel a, ⁎ , Abdallah Gameel a , Gamal T.A. Ebid a , Eman R. Radwan b , Mostafa F. Mohammed Saleh c , Raafat Abdelfattah d,e a Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt b Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt c Clinical Hematology Unit, Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt d Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt e Bone Marrow Transplantation Unit, Nasser Institute Hospital for Research and Treatment, Cairo, Egypt ARTICLE INFO Keywords: HSCT GVHD Cytokine gene polymorphism IL-10 IFN-γ TGF-β1 ABSTRACT Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplanta- tion (HSCT); cytokines are recognized as important mediators in its pathogenesis. In this study we investigated the role of cytokine gene polymorphisms on HSCT outcome. A total of 106 patient and 98 donors were geno- typed by polymerase chain reaction sequence specific primers (PCR-SSP) based assay for tumor necrosis factor- α-308 (TNFα -308), interleukin (IL)-6-174, IL-10-1082, -819, -592, Interferon-γ+874 (IFN-γ+874), and transforming growth factor-β1 (TGF-β1) codon10 and 25 polymorphisms. Except one in each category, all patients and donors were TNFα -308 high producers and the majority were IL-6-174 high producers (93.3% and 90.8% respectively); a pattern that would alleviate any potential biological impact. Patient's IFN-γ+874 showed sig- nificant association with the development of chronic GVHD. Patients with IFN-γ +874 high producer showed an 8 folds likelihood to develop chronic GVHD as compared to those with IFN-γ+874 low producer predicted phenotype (95% CI: 1.59-40.2, p = 0.01). Patient's TGFβ1-codon 10 and 25 high/intermediate producers showed a lower incidence of acute GVHD though it did not achieve statistical significance (p = 0.065) on ac- count of the low frequency of this genotype in our patients and donors (11.4 and 8.2% respectively). Other factors contributing to risk of GVHD included older age for both acute and chronic (p = 0.01 and 0.02 re- spectively) with age 24 as the best discriminating cutoff; CD34+ cell dose for chronic GVHD (p = 0.045) with a dose of 8 × 10 6 /kg as the best discriminating cutoff; and conditioning regimen with Flu/Bu associated with the lowest incidence of acute GVHD (p = 0.003) and no impact on chronic GVHD. In conclusion the current study further indicates a potential role of some cytokine gene polymorphisms in the development of GVHD. The relative distribution of high and low producer genotypes in different ethnic groups contributes to their biological impact in different populations. 1. Introduction Graft versus host disease (GVHD) remains a source of significant morbidity and mortality in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). The pathogenesis of both acute and chronic GVHD is well understood with cytokines at the core of the interactive immune reactions [1]. According to the three-phase model of acute GVHD, inflammatory cytokine (TNF-α, IL-6 and IL-1) secretion is triggered by the con- ditioning regimen. This is followed by donor T cells proliferation and secretion of IL-2 and IFN-γ which induce TNFα and IL-1 production by primed additional mononuclear phagocytes. Lastly, activated Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells induce target tissue damage through cell-mediated cytotoxicity [2–6]. Chronic GVHD starts with the expansion of donor T cells in response to alloantigens or au- toantigens that are unchecked by normal thymic or peripheral me- chanisms of deletion. The T cells induce damage to target organs either directly through cytolytic attack, inflammatory cytokines (TNF-α) and fibrosis, or by promoting B-cell activation and production of auto-an- tibodies [7,8]. Several studies investigated the cytokine(s) levels as a potential factor to diagnose and/or predict the occurrence or severity of GVHD https://doi.org/10.1016/j.cyto.2018.05.003 Received 20 October 2017; Received in revised form 10 April 2018; Accepted 7 May 2018 ⁎ Corresponding author at: National Cancer Institute, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt. E-mail address: Azza.kamel@nci.cu.edu.eg (A.M. Kamel). Cytokine xxx (xxxx) xxx–xxx 1043-4666/ © 2018 Elsevier Ltd. All rights reserved. Please cite this article as: Kamel, A.M., Cytokine (2018), https://doi.org/10.1016/j.cyto.2018.05.003