The donor genetic determinant of human thymopoiesis rs2204985 is associated with acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients

The rs2204985 single-nucleotide genetic polymorphism is a common genetic variant located within the T-cell receptor locus that influences thymopoiesis, with the GG genotype presenting higher thymic function than AA counterparts. Recent reports have presented discordant results regarding its effect on the clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, evaluation of independent cohorts is warranted. Here, we further investigate the donor polymorphism impact on patient outcome after allo-HSCT in a single-center observation case report from Karolinska University Hospital, Sweden. We retrospectively evaluated 521 adult patients and investigated the impact of the donor rs2204985 genotype on their clinical outcomes post-transplantation. We observed no significant effect of donor genotype on mortality or relapse. The GG genotype was associated with a higher incidence of severe (IIb-IV) acute graft-versus-host disease (GVHD) as compared with AG/AA (P = 0.008), but with no impact on chronic GVHD incidence. The same effect is observed in a subgroup of patients treated with unrelated donors (P = 0.02) but not with human leukocyte antigen-matched sibling donors. A multivariate analysis confirmed the impact of the rs2204985 genotype (P = 0.009) independently of other parameters, including recipient age or sex. Our data suggest that, in this single-center cohort, the donor rs2204985 AA/AG genotype, despite not significantly affecting relapse or survival, is associated with lesser risk of acute GVHD development. ©2025 International Society for Cell & Gene Therapy. Published by Elsevier Inc.