Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). While HLA compatibility is a key determinant, increasing evidence suggests that non-HLA immune gene polymorphisms, particularly those in cytokine genes, contribute to GVHD risk. This study seeks to validate in a pediatric population, cytokine-related single nucleotide polymorphisms (SNPs) associated with acute GVHD (aGVHD) and analyze them in combination with the previously identified HLA risk alleles. Pediatric HSCT recipients were recruited from the CHU Sainte-Justine biobank and a prior European Society for Blood and Marrow Transplantation (EBMT) multicenter study. Twenty-five SNPs in 12 cytokine genes were selected based on published associations with aGVHD. Genotypes were obtained for discovery (n=87) and replication (n=154) cohorts and association analyses were conducted in each cohort and in the combined dataset. Two SNPs, IL1B rs1143627 and IL17A rs8193036, were significantly associated with increased risk of aGVHD II-IV (p=0.019 and p<0.001, respectively). These associations were strongest in HLA-matched unrelated-donor-recipient pairs for IL1B rs1143627 (p=0.015) and in all HLA-matched pairs for IL17A rs8193036 (p=0.004). Notably, carriers of one or both risk alleles combined with HLA-B*15:01 had a markedly elevated risk (HR: 2.14 CI:1.41 - 3.25, p=6×10⁻⁶). These findings highlight the relevance of non-HLA genetic variants in aGVHD pathogenesis. Incorporating cytokine SNP profiles, especially IL1B rs1143627 and IL17A rs8193036, alongside HLA typing may improve donor selection and guide individualized aGVHD prophylaxis. • IL1B rs1143627 and IL17A rs8193036 are associated with increased risk of aGVHD • Carriers of one or both SNPs combined to HLA-B*15:01 had a markedly elevated risk • Cytokine SNP profiles with HLA typing may guide individualized aGVHD prophylaxis
Mootoosamy et al. (Sun,) studied this question.