Impact of interleukin-10 polymorphisms (-1082 and -3575) on the survival of patients with lymphoid neoplasms.

Identifier:  imarina:5121728

Handle: https://hdl.handle.net/20.500.11797/imarina5121728

Authors:  Domingo-Domènech E; Benavente Y; González-Barca E; Montalban C; Gumà J; Bosch R.

Abstract:
Background and Objectives Single-nucleotide polymorphisms (SNP) in interleukin-10 (IL-10) genes can influence immune responses, which may affect the outcome of patients with lymphoid neoplasms. The aim of this study was to explore the association between polymorphisms of IL-10-1082A>G and IL-10-3575T>A with the overall survival in patients with lymphoid neoplasms.Design and Methods We analyzed two IL-10 SNP (−1082 and −3575) in 472 consecutive cases with lymphoid neoplasms. Genotypes were tested for association with overall survival and classical prognostic factors by multivariate analysis. Haplotype analysis was carried out using the haplostats package implemented in R software. The implications for survival of patients with lymphoma were evaluated using multivariate analysis.Results Lymphoma patients with the IL-10-3575T>A genotype had a better overall survival (p= 0.002), as did the subgroup with non-Hodgkin’s lymphoma (NHL) (p=0.05). Patients with the IL10-1082GG genotype had a better median overall survival (p=0.05). When both genotypes were included in a multivariate analysis, IL-10-3575AA genotype was the only independent prognostic factor for survival (HR=0.20, 95%CI 0.05–0.92). Patients with the IL-10-1082 and -3575 G-A/G-A diplotype had a longer overall survival (p=0.003) and this combination appeared to be an independent prognostic factor for survival (HR:0.26; 95%CI 0.08–0.83).Interpretation and Conclusions The IL-10-3575A/A genotype was identified as a marker of favorable survival. Because the IL-10-1082 and -3575 G-A/G-A diplotype was also identified as an indicator of longer survival, we cannot exclude the potential additive role of the IL-10-1082GG genotype. These results need to be replicated in larger series and examined in different NHL subtypes. Interleukin-10 (IL-10) is a cytokine normally produced by activated T cells, monocytes, B cells and thymocytes. It contributes to antigen- or mitogen-driven B-cell differentiation and acts as a growth factor. IL-10 is also an immune response modulator. Dysfunctions in the immune system are thought to be the underlying basis of lymphomagenesis.1 Several studies have shown the possible involvement of IL-10 in the pathogenesis of lymphoid malignancies, as well as its association with prognosis.2–4 Dysregulation of IL-10 production appears to play a role in lymphoproliferative disease and it is hypothesized that polymorphisms in the IL-10 gene promoter, which predispose an individual to high IL-10 levels, may be more frequent in patients with lymphoma than among the normal population. It has also been described that patients with high IL-10 production have a worse prognosis.3, 5, 6 A number of polymorphisms of the IL-10 gene promoter have been described. These include two biallelic polymorphisms at positions −1082 (G to A substitution), and −3575 (T to A substitution). Briefly, IL-10-1082A→G is localized in the proximal region of the IL-10 promoter between −4kb and −1.1 kb and IL-10-3575T→A is localized in the distal region of the promoter between −1.3 kb and −4.0 kb. A number of studies have reported that IL-10-1082G7 and IL-10-3575T alleles are associated with high IL-10 production.8 Previous studies have evaluated whether polymorphisms in IL-10-3575T→A and IL-10-1082A→G9 are associated with an increased risk of non-Hodgkin’s lymphomas. Cunningham et al.9 observed that the frequency of the low IL-10 producing AA allele (at position −1082) was significantly higher in patients with aggressive lymphomas compared to in controls. However, in a larger study group, Lech-Maranda E et al.2 found that the frequency of IL-10-1082G allele was higher in patients with diffuse large B-cell lymphoma than in controls. Most recently, Rothman et al.10 identified genotypes AA or TA at position −3575 of IL-10 to be associated with an increased risk of non-Hodgkin’s lymphoma in the largest pooled analysis to date. Few studies have yet analyzed the impact of IL-10 polymorphisms on the prognosis of patients with lymphoma. Only one, by Lech-Maranda E et al.,2 found that patients carrying the IL-10-1082G allele had higher complete remission rates, 5-year freedom from progression, and better overall survival when compared to patients carrying the IL10-1082AA genotype. The aim of this study was, therefore, to explore the association between polymorphisms of IL-10-1082A→G and IL-10-3575T→A with the overall survival in patients with lymphoid neoplasms.