ABSTRACT: The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for de novo T cell generation in thymus and peripheral T cell homeostasis. In this study, we investigated the impact of the single nucleotide polymorphism rs6897932 in the IL-7 receptor ?-chain (IL-7R?) which has previously been associated with several autoimmune diseases. We included 460 patients undergoing allogeneic HSCT after a myeloablative conditioning. Patients had a median age of 26.3?years (0.3-67.0?years), and 372 (80.9%) underwent HSCT for malignant diseases. Donors were matched sibling donors (n?=?147), matched unrelated donors (n?=?244) or mismatched unrelated donors (n?=?69), and the stem cell source were either bone marrow (n?=?329) or peripheral blood (n?=?131). DNA from donors was genotyped for the IL-7R? single nucleotide polymorphism (SNP) rs6897932 using an allele-specific primer extension assay (CC: n?=?252, CT: n?=?178, TT: n?=?30). The donor T allele was associated with a higher risk of grades III-IV aGVHD (HR?=?2.0, 95% CI?=?1.1-3.8, P?=?0.034) and with significantly increased risk of extensive cGVHD (HR?=?2.0, 95% CI?=?1.1-3.6, P?=?0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR?=?2.4, 95% CI?=?1.2-4.3, P?=?0.0068). Numbers of T cells were significantly higher on day +60 in patients receiving a rs6897932 TT graft (CD3+: 109% increase, P?=?0.0096; CD4+: 64% increase, P?=?0.038; CD8+: 133% increase, P?=?0.011). Donor heterozygosity for the T allele was associated with inferior overall survival (HR?=?1.7, 95% CI?=?1.2-2.3, P?=?0.0027) and increased treatment-related mortality (HR?=?2.3, 95% CI?=?1.3-4.0, P?=?0.0047), but was not associated with the risk of relapse (P?=?0.35). In conclusion, the IL-7R? rs6897932 genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality following HSCT. These findings indicate that IL-7R? SNP typing of donors may optimize donor selection and facilitate individualization of treatment in order to limit treatment-related complications.
