Donor Genotype in the Interleukin-7 Receptor α-Chain Predicts Risk of Graft-versus-Host Disease and Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Katrine Kielsen, Christian Enevold, Carsten Heilmann, Henrik Sengeløv, Anders Elm Pedersen, Lars P. Ryder, Klaus Müller

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 forde novoT cell generation in thymus and peripheral T cell homeostasis. In this study, we investigated the impact of the single nucleotide polymorphismrs6897932in the IL-7 receptor α-chain (IL-7Rα) 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-7Rα single nucleotide polymorphism (SNP)rs6897932using 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 ars6897932TT 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-7Rαrs6897932genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality following HSCT. These findings indicate that IL-7Rα SNP typing of donors may optimize donor selection and facilitate individualization of treatment in order to limit treatment-related complications.