The Genotype of the Donor for the Polymorphism A7488G of the IL-17 Gene Influences relapse and survival After HLA-Identical Related Stem Cell Transplantation.
Authors: Martínez-Laperche C. , Noriega V. , Herraiz Adela , Bosh A. , Guillem V. , Nieto Jose B , González M. , De La Camara Rafael , Brunet S. , Jimenez-Velasco A. , Espigado Ildefonso , Llamas Juan Carlos Vallejo , Sampol Antonia , Serrano David , Gayoso Jorge , Balsalobre Pascual , Solano Carlos , Gallardo David , Diez-Martín Jose Luis ,   Ismael Buno on behalf of the Spanish Group of HSCT
Published: October 2019

Abstract
Abstract 1302

Introduction:
Interleukin 17 (IL-17) is a pro-inflammatory cytokine secreted by CD4+ helper T (TH) cells, TH17 cells. IL-17F is the most recently discovered member of the IL-17 cytokine family. IL-17F induces several cell types to express cytokines, chemokines, growth factors, and adhesion molecules, which are crucial molecules in leukocyte recruitment and activation. On this basis, IL-17F has been associated with the pathogenesis of multiple autoimmune diseases. Allele G for the polymorphism A7488G seems to play a protective role for the development of such diseases. However, no data is available about the possible impact of this polymorphism on the development of complications after allogeneic stem cell transplantation (allo-SCT).

Objective:
To analyze the influence of the donor (Dn) and recipient (Rc) genotype for the polymorphism A7488G in the IL-17F gene on the outcome of HLA-identical related allo-SCT.

Material and Methods:
The study comprised 143 allo-SCT patients and their donors (286 samples) included in the Spanish Group for Hematopoietic Stem cell Transplantation (GETH) DNA bank. Genomic DNA was purified from peripheral blood samples obtained, after written informed consent, from patients pre-SCT and donors. The A7488G polymorphism of the IL-17F gene was analyzed by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) following the procedure developed by Tahara et al. (J Clin Immunol 2008, 28:44-49). Results were analyzed using the Pearson's Chi-square Test.

Results:
In accordance with previous reports, allele G was present in a reduced number of individuals, 30/286 (10.5%) corresponding to 19/143 Allo-SCT (13.3%). The genotypes of the Dn were 129/143 (90.2%) AA and 14/143 (9.8%) AG, while those of the Rc were 127/143 (88.8%) AA and 16/143 (11.2%) AG. No Dn or Rc with GG genotype was found. Dn and Rc genotype combinations were as follows: DnAA-RcAA, 124/143 (86.7%); DnAG-RcAG, 11/143 (7.7%), DnAA-RcAG, 5/143 (3.5%), DnAG-RcAA, 3/143 (2.1%). The genotype of the donor influenced transplant outcome in terms of relapse (35/129 (27.1%) when the donor was AA vs. 1/14 (7.1%) when the donor was AG; p=0.119) and survival (exitus 64/129 (49.6%) when the donor was AA vs. 3/14 (21.4%) when the donor was AG; p=0,045). No association between Dn or Rc genotype and graft versus host disease (acute or chronic) or other complications was observed. The differences observed in relapse and survival according to the genotype of the donor, were especially true for AG genotype patients (no significant differences were observed in AA genotype patients). In fact, relapse (3/5 (60%) when the Dn was AA vs. 0/11 (0%) when the Dn was AG; p=0.004) and survival (exitus 5/5 (100%) when the Dn was AA vs. 1/11 (9,1%) when the Dn was AG; p<0.001) showed large differences depending on the genotype of the donor in this subgroup of patients. Kaplan-Meier estimates (Figure 1) showed a trend to a better disease free survival (EFS; not reached (NR) vs. 692 days p=0.083)) and overall survival (OS; NR vs. 913 days p=0.175) in patients transplanted with AG genotype Dn and a statistically significant better EFS (NR vs. 114 days p=0.014) and OS (NR vs. 193 days p=0.022) when AG genotype patients were transplanted with AG genotype Dn.

Conclusions:
The polymorphism A7488G of the IL-17F gene, which causes a His-to-Argsubstitution at amino acid 161 (H161R), influences the outcome of HLA-identical related allo-SCT. The presence of allele G in the Dn had a favourable effect on transplant outcome, in terms of lower relapse rate and better survival. Analysis of a larger set of Rc/Dn pairs is ongoing which will allow to increase the number of individuals harboring allele G and, ultimately, to confirm the results shown here. In such case, genotyping for the polymorphism A7488G of the IL-17F gene could aid in donor selection or drive a risk-adapted management of transplanted patients.

Disclosures:
No relevant conflicts of interest to declare.