Cytokine gene polymorphisms and graft-versus-host disease in children after matched sibling hematopoietic stem cell transplantation: a single-center experience

Abstract

Various polymorphisms in cytokine genes have recently been investigated as candidate risk factors in allogeneic hematopoetic stem cell transplantation (allo-HSCT). We retrospectively analyzed specific polymorphisms in genes for interleukin (IL)-10, IL-6, tumor-necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in a pediatric cohort of 57 histocompatibility leucocyte antigen (HLA)-identical sibling myeloablative transplants. Both recipient and donor genotypes were tested for association with graft-versus-host disease (GVHD) by statistical methods including Cox regression analysis. We found a significant association between the IL-10 promoter haplotype polymorphisms at positions -1082, -819 and -592 with the occurrence of severe (grades III-IV) acute GVHD (aGVHD). Recipients with the haplotype GCC had a statistically significant decreased risk of severe aGVHD (hazard risk (HR)=0.20, 95% confidence interval (CI): 0.06-0.67) in comparison with patients with other IL-10 haplotypes (P=0.008). Transplant-related mortality at 1 year was significantly lower in recipients with this haplotype (HR=0.17, 95% CI: 0.012-0.320) versus other IL-10 haplotypes (P=0.03), whereas overall survival was not influenced by IL-10 haplotype polymorphisms. In multivariate analysis, the presence of the IL-10 GCC haplotype was found as the only variable associated with a statistically significant decreased hazard of severe aGVHD development (P=0.02, HR=0.21, 95% CI: 0.05-0.78). These results suggest that pediatric patients possessing the IL-10 GCC haplotype may be protected from the occurrence of severe aGVHD in the setting of matched sibling HSCT.

Figure 1

Kaplan–Meier curve shows the probability of overall survival for the entire cohort.

Figure 2

Severe aGVHD (grades III–IV) in relation to the presence or absence of the IL-10 GCC haplotype in the recipients. Recipients with the IL-10 GCC haplotype had decreased risk to develop aGVHD grades III–IV compared to recipients without it (P=0.008). aGVHD, acute graft-versus-host disease.

Figure 3

TRM at 1 year after transplantation in relation to the presence or absence of the IL-10 GCC haplotype in the recipients. The probability of TRM at 1 year post-transplantation was significantly lower when the GCC haplotype was present in the recipient compared with when the haplotype was absent from the recipient (log-rank test: P=0.03). TRM, transplant-related mortality.