Cytokine gene polymorphisms are well know to be associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. They seem to play an important role in allogeneic stem cell transplantation (allo-SCT), mostly in the incidence and severity of graft-versus -host disease (GVHD) which is one of the most common serious complications of allo-SCT. Interleukin-6 (IL-6) is a proinflamatory cytokine known to be implicated in the pathogenesis of aGVHD with increasing serum levels during the development. The IL6−174 (G/C) single nucleotide polymorphism (SNP), localized in the promoter region (7p21) has been linked to in vitro and in vivo productions, associating the presence of allele G with significantly higher levels of IL-6 and a trend to have higher grades of aGVHD.
To analyze the influence of Donor (D) and Recipient (R) genotype for the polymorphism IL6−174 (G/C) on the outcome of HLA-identical related stem cell transplantation.
The study comprised 171 allo-SCT (342 D/R samples) included in the Spanish Group for Haematopoietic Stem cell Transplantation (GETH) DNA bank. Genomic DNA was purified from peripheral blood samples obtained pre-SCT from patients and donors, after written informed consent. The IL6−174 (G/C) SNP genotype was determined by allele-specific PCR (Cavet et al, Blood 98, 2001). Results were analyzed using the Pearson's Chi-square Test and survival estimation by Kaplan-Meier curves.
Genotypes for D and R as well as D/R combinations (table 1), were in accordance with previous reports. Homozygous recipients for IL6−174GG polymorphism showed a trend to higher incidence of grade III-IV aGVHD than those with other genotypes (19.9% vs 9.1%) p=0.14. No significant differences were found in terms of cGHVD, relapse or mortality rates. On the other hand, patients transplanted from homozygous GG Donors showed a higher incidence of extense cGVHD (20/52 (38%) vs 21/87 (24%) p=0.07), lower relapse rates (10/59 (23.8%) vs 32/105 (76.2%) p=0.041) and better global mortality rates (23/62 (36.9%) vs 51/106 (69%) p=0.11). Survival analysis with Kaplan-Meier curves in this group of patients (IL6−174GG homozygotes in the Donor) revealed a lower cumulative incidence of relapse (CIR) (NR vs 567 days p=0.028) a better event free survival (EFS) (732 days vs 380 days p=0.02) and showed a trend to a better overall survival (OS) (1235 days vs 836 days p=0.157); (Figure1).
IL6 cytokine is known to be implicated in the pathogenesis of aGHVD with increasing serum levels during its development. The presence of allele G for the polymorphism of IL6−174(G/C) which is associated with higher levels of IL6, has shown to influence the outcome of our cohort of HLA-identical related stem cell transplantation. Since acute GHVD is mainly influenced by R genotype and chronic GHVD by D genotype, the present study revealed that homocigous presence in the R of allele G was associated with higher incidence of aGHVD. Moreover when this allele is homozigously present in the D, patients show greater extense cGHVD and better EFS and OS. Genotyping for this polymorphism could aid in D selection or even more interestingly drive a risk-adapted management of transplanted patients.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.