Clinical Impact of Cytokine and Chemokine Genes Polymorphisms on Outcome After Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the possible curative therapy for many hematological malignancies and other congenital or acquired disorders. Despite significant progress, this procedure is still associated with substantial morbidity and mortality. Various pretransplantation and transplantation-related clinical risk factors have been implicated, but so far there is no method to estimate the occurrence and severity of transplant-related complications. The most common complication after allo-HSCT which affects survival remains graft versus host disease (GvHD). Cytokines and chemokines are major mediators in the inflammation and immune responses, especially in alloreactivity, which plays major role during GvHD. Single nucleotide polymorphisms (SNPs) in genes coding cytokines and chemokines have been shown to influence GvHD and outcome after allo-HSCT. This study aimed to determine association between SNPs in the: CCL5/RANTES (CC-chemokine ligand 5/Regulated upon Activation, Normal T cell Expressed and Secreted) promoter gene at positions -28C/T (rs1800825) and -403C/T (rs2107538), and IL-2 at position -330 G/T (rs2069762), IL-10 at positions -1082 A/G (rs1800896) and -592 A/C (rs1800872), and TNFalfa at position -308 A/G (rs1800629) with the outcome of allo-HSCT performed between August 2003 and April 2009 in our center.

The allelic variants of these 6 SNPs were determined in 64 patient/donor pairs by real-time polymerase chain reaction (TaqMan-MGB). Patients characteristics were: median age 36 (range 18–65), underlaying diseases-hematologic malignancies in 62 and aplastic anemia – in 2 cases. Donors were HLA-identical sibling-in 46 and unrelated-in 18 transplants, the median age-37 (range 14–65). The studied end points were GvHD, oral mucositis, haemorrhagic cystitis, toxicity and venooclusive disease (VOD) of the liver and survival.

The allelic distribution of examined SNPs was similar to that reported in Caucasoid population. Acute-GvHD was recognized in 31/64 (48,4%) and chronic-in 34/64 (53%) of patients. Overall survival in analysed group was 56%. Our study revealed significant correlation between the occurrence and severity of aGvHD and the -403C/T SNP in patients (TT and CT vs CC genotypes-41,7% vs 31,4% respectively, P=0.025), IL-10-592 A/C in recipients (AA genotypes–80%, P=0.050) and IL-2–330 G/T in patients (GG and GT vs TT genotypes respectively-40,6% vs 28,1%, P=0.034) and their donors (GG and GT vs TT genotypes respectively-11% vs 3,6%, P=0.049). Correlation between aGvHD and differences in donors genotypes in the -403C/T SNP was indicative of the trend (P=0.095). Besides we found a significant correlation between liver toxicity after conditioning regimen and SNPs: TNFalfa -308 A/G in patients (GG vs AA and AG–50% vs 45%, P=0.043) and donors (GG vs AA and AG–52% vs 40%, P=0.032) and IL-10-1082 A/G (GG vs AA and AG–77,8% vs 43,6%, P=0.003). Moreover our results revealed trend toward correlation between the -403C/T SNP in recipients and development of VOD (TT and CT vs CC genotypes-30,8% vs 11,8%, P=0.070) and haemorrhagic cystitis (30,8% vs 17,6%, P=0.071). The only statistically significant correlation for -28C/T SNP was increased overall survival obtained by the Kaplan-Meier method for patients carrying CT genotype (100% vs 51,7% for TT-homozygotes, P=0.048). Besides we couldn't find any correlation between examined SNPs and the rest of analysed end points (P=ns).

Our data revealed that SNPs in the CCL5/RANTES, IL-10, IL-2 and TNFalfa promoter genes are correlated with aGvHD, toxic complications and overall survival after allo-HSCT. These findings confirmed some previously published data, but many results remains variable between investigators, so should be studied prospectively and in the larger group of patients.

No relevant conflicts of interest to declare.