IL1B rs1143627 and IL17A rs8193036 in the risk of Acute Graft Versus Host Disease in pediatric HSCT

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.