Impact of Interleukin-10 Gene Promoter Polymorphisms on Clinical Course of Chronic Lymphocytic Leukemia

Background: Interleukin-10 (IL-10) is an important immunoregulatory cytokine modulating the balance between cell-mediated and humoral response. It has been suggested that dysregulation and different IL-10 level resulting from single-nucleotide polymorphisms (SNPs) in IL-10 gene promoter play a role in pathogenesis of lymphoid disorders, and may increase a risk of non-Hodgkin lymphomas (NHL) development, especially diffuse large B-cell lymphoma subtype. The aim of this study was to investigate whether functionally important IL-10 promoter region SNPs IL-10: −1082A>G and IL-10: − 3575T>A contribute to the incidence and clinical course of B-cell chronic lymphocytic leukemia (CLL).

Patients and Methods: We genotyped IL-10: −1082A>G and IL-10: − 3575T>A SNPs in 85 patients with B-CLL and 94 ethnically-matched healthy individuals by direct sequencing using 3130xl Genetic Analyzer (Applied Biosystems). Sequence data were based on the NCI SNP500 website http://snp500cancer.nci.nih.gov. Haplotype analysis was performed using version 2.0.2 PHASE software (http://www.stat.Washington.edu/stephens/). For the clinical features, p values were calculated using χ² test. Survival probabilities were estimated using the Kaplan-Meier method and comparison of survival was based on log-rank testing.

Results: The IL-10: −1082A>G or IL-10: −3575T>A allelic frequencies and distributions were consistent with Hardy-Weinberg equilibrium, and did not differ significantly between CLL patients and the control group. Four distinct haplotypes, including IL-10: −1082G, −3575A, IL-10: −1082A, −3575T, IL-10: −1082G, − 3575T, and IL-10: −1082A, −3575A, inferred in healthy controls and CLL patients. There were no significant differences in estimated frequencies of these haplotypes between CLL patients and controls. No association was found between IL-10: −1082A>G or IL-10: − 3575T>A allelic, genotype or haplotype distribution and clinical characteristics of CLL patients at diagnosis, including age, clinical stage according to Rai classification, surface CD38 expression, serum LDH and β₂-microglobulin levels. In patients with IL-10: − 1082G allele (IL-10: −1082GG or IL-10: −1082GA genotypes) there was a trend towards higher frequency of autoimmune complications during CLL course as compared to those carrying IL-10: −1082AA genotype (13% vs 0%, p=0.04, χ² test). The patients with IL-10: −1082G allele had significantly shorter time from diagnosis to treatment (log-rank test, p=0.02) as compared to individuals carrying IL-10: −1082AA genotype. However, neither of assessed IL-10 SNPs was associated with response to first-line treatment or freedom from progression time. With a median follow-up of surviving patients of 80 months (range 8–209), no correlation was found between IL-10: −1082A>G or IL-10: −3575T>A alleles, genotypes or haplotypes and overall survival in CLL patients.

Conclusions: The study suggests the influence of IL-10: −1082G allele, predisposing to higher IL-10 production, on activation of immune system towards more aggressive course of CLL requiring earlier treatment intervention. Similarly to other low-grade NHL studies, our findings did not support an important role of IL-10 SNPs in CLL occurrence and survival however larger studies are needed to confirm these results.