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

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00109

DOI=10.3389/fimmu.2018.00109

ISSN=1664-3224

ABSTRACT=<p>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 <italic>de novo</italic> T cell generation in thymus and peripheral T cell homeostasis. In this study, we investigated the impact of the single nucleotide polymorphism <italic>rs6897932</italic> 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 (<italic>n</italic> = 147), matched unrelated donors (<italic>n</italic> = 244) or mismatched unrelated donors (<italic>n</italic> = 69), and the stem cell source were either bone marrow (<italic>n</italic> = 329) or peripheral blood (<italic>n</italic> = 131). DNA from donors was genotyped for the IL-7Rα single nucleotide polymorphism (SNP) <italic>rs6897932</italic> using an allele-specific primer extension assay (CC: <italic>n</italic> = 252, CT: <italic>n</italic> = 178, TT: <italic>n</italic> = 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, <italic>P</italic> = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1–3.6, <italic>P</italic> = 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, <italic>P</italic> = 0.0068). Numbers of T cells were significantly higher on day +60 in patients receiving a <italic>rs6897932</italic> TT graft (CD3+: 109% increase, <italic>P</italic> = 0.0096; CD4+: 64% increase, <italic>P</italic> = 0.038; CD8+: 133% increase, <italic>P</italic> = 0.011). Donor heterozygosity for the T allele was associated with inferior overall survival (HR = 1.7, 95% CI = 1.2–2.3, <italic>P</italic> = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3–4.0, <italic>P</italic> = 0.0047), but was not associated with the risk of relapse (<italic>P</italic> = 0.35). In conclusion, the IL-7Rα <italic>rs6897932</italic> 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.</p>