Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT

• Published in: Bone marrow transplantation (Basingstoke) Vol. 56; no. 11; pp. 2697 - 2704
• Main Authors: Ansari, Marc, Petrykey, Kateryna, Rezgui, Mohamed Aziz, Del Vecchio, Veronica, Cortyl, Jacques, Ameur, Milad, Nava, Tiago, Beaulieu, Patrick, St-Onge, Pascal, Mlakar, Simona Jurkovic, Uppugunduri, Chakradhara Rao S., Théoret, Yves, Bartelink, Imke H., Boelens, Jaap-Jan, Bredius, Robbert G. M., Dalle, Jean-Hugues, Lewis, Victor, Kangarloo, Bill S., Corbacioglu, Selim, Sinnett, Daniel, Bittencourt, Henrique, Krajinovic, Maja
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Nature Publishing Group
• Subjects: 45; 45/23; 45/43; 692/308/2056; 692/499; Acute Disease; Bone marrow; Bone marrow transplantation; Care and treatment; Cell Biology; Cell differentiation; Cell proliferation; Chemokines; Child; Cytokines; Gastrointestinal system; Gastrointestinal tract; Genetic aspects; Genetic factors; Genetic Predisposition to Disease - etiology; Genetic variability; Genotypes; Graft versus host disease; Graft versus host reaction; Graft vs Host Disease - genetics; Hematology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Histocompatibility antigen HLA; Humans; Inflammation; Inflammatory response; Internal Medicine; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Patients; Pediatrics; Public Health; Risk factors; Single-nucleotide polymorphism; Stem cell transplantation; Stem Cells; Tissue Donors; Transplantation; Transplantation Conditioning - adverse effects; Transplants & implants; Switzerland
• ISSN: 0268-3369; 1476-5365; 1476-5365
• DOI: 10.1038/s41409-021-01386-8

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort ( n  = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group ( n  = 168). Significant associations were replicated for ERC1 rs1046473 , PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals ( p  = 0.03), bone marrow stem cells recipients ( p  = 0.007), and serotherapy-negative patients ( p  = 0.004). NOP9, PLEK , and SPRED1 effects were modulated by stem cell source, and serotherapy ( p  < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates ( p  = 0.02 and p  = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.