Toll‐Like Receptor Polymorphisms Influence Graft‐Versus‐Host Disease and Infection Risk After Single‐Unit Cord Blood Transplantation for Adults

Background Toll‐like receptors (TLRs) play a critical role in innate immunity by recognizing pathogen‐associated and damage‐associated molecular patterns. Genetic polymorphisms in TLR genes can modulate immune responses and have been implicated in the outcomes of allogeneic hematopoietic cell transplantation (HCT). However, their impact on clinical outcomes after single‐unit cord blood transplantation (CBT) remains unclear. Methods We retrospectively analyzed adult patients who underwent single‐unit CBT at our institution between January 2005 and March 2023 with available recipient or donor DNA samples. Genotyping of TLR2 (rs3804099), TLR3 (rs3775291), TLR5 (rs5744174), and TLR9 (rs352140) was performed. Associations between recipient and donor TLR polymorphisms and transplantation outcomes—including hematopoietic engraftment, acute and chronic graft‐versus‐host disease (GVHD), infectious complications, relapse, non‐relapse mortality (NRM), and survival—were evaluated using univariate and multivariate analyses. Results Donor TLR2 rs3804099 and TLR9 rs352140 variants were associated with platelet engraftment rates. Recipient TLR3 rs3775291 TT genotype correlated with increased risk of grades II–IV acute GVHD and invasive fungal infection, while donor TLR5 rs5744174 GG/GA genotypes were linked to higher chronic GVHD incidence. Recipients with TLR9 rs352140 CC genotype exhibited higher bacterial bloodstream infection and NRM rates. No significant associations were found between TLR polymorphisms and overall or disease‐free survival. Cytokine analyses revealed distinct profiles according to TLR polymorphisms, including elevated MCP‐1 and IL‐18 in TLR5 GG/GA donors and lower IL‐8 in TLR9 CC recipients, suggesting mechanistic relevance. Conclusions Our findings demonstrate that recipient and donor polymorphisms in TLR3, TLR5, and TLR9 genes affect GVHD development and infection risk following single‐unit CBT in adults. Understanding these genetic influences may guide personalized approaches to improve CBT outcomes.