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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 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)  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-7Rα  rs6897932  genotype 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.

frontiers in immunology

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