TNF-α -308 G>A and IL10 -1082A>G polymorphisms as potential risk factors for lymphoproliferative disorders in autoimmune rheumatic diseases

Abstract

Background: Chronic inflammation with sustained unregulated immune stimulation in autoimmune rheumatic diseases (ARD) may be a risk factor for developing lymphoproliferative disorders (LPD). Markers of ARD activity as high erythrocyte sedimentation rate or erosive joint diseases and the development of B-symptoms were accounted as risk factors for LPD development. We investigated the association of five inflammatory cytokine genes single nucleotide polymorphisms (SNPs): TNF-α-308G>A; TGF-β1 gene codon 10 T>C and 25 G>C; IL-10 promoter SNPs-1082 A>G,-819T>C, and-592A>C; IL-6-174G>C; and IFN-γ 874 T>A with the risk of LPD development in ARD patients. The study was conducted on 70 patients divided into group I, 25 ARD patients diagnosed as RA (n = 15) and SLE (n = 10) and with no history of malignancy; group II, 25 patients diagnosed with LPD and had no ARD; and group III, 20 patients diagnosed with both diseases: ARD and LPD. Cytokine genotyping was analyzed by PCRsequence-specific primer (PCR-SSP). Results: ARD+LPD patients had significantly higher frequency of TNF-α-308A allele and AA+AG genotype (high TNF-α producers) and IL-10-1082A allele and AA genotype (low IL-10 producers) than ARD patients (p = 0.003, p = 0.024, p = 0.003, p = 0.03, respectively) with a significantly increased risk of LPD development in ARD patients expressing the corresponding alleles and genotypes. No significant differences were detected in the distribution frequency of either TGF-β1, IL-6, or IFN-γ SNPs between groups I and III or any of the studied SNPs between groups II and III. The distribution frequency of IL-10 ATA haplotype was significantly increased in group III as compared to group I (p = 0.037). Conclusion: The significantly increased frequency of the high-TNF-α-and low-IL-10-producing alleles and genotypes in ARD patients may participate in the provision of a proinflammatory milieu that eventually increases the risk of LPD development.

Association of TNF–α rs1800629 with Adult Acute B-Cell Lymphoblastic Leukemia

“…In patients with NHL, high levels of TNF–α were been found to be associated with negative prognosis, high frequency of relapse and reduced survival [ 10 ]. Similarly, it was reported that the G>A genotype and A allele of rs1800629 SNP increase susceptibility to NHL and autoimmune rheumatic disease with lymphoproliferative disorders [ 14 , 23 ].…”

“…It has been documented that the A allele of the altered TNF–α promotor region due to rs1800629 SNP leads to higher transcriptional activity than its ancestral G allele, causing increased production of TNF–α by B and T cells [ 23 , 24 , 25 , 26 ]. High levels of TNF–α have been found in patients with childhood ALL in comparison to normal control subjects [ 27 ].…”

Association of Genetic Polymorphism of Tumor Necrosis Factor-α in the Development of Coronary Heart Disease in Elderly Patients

“…Genetic studies have also found that the allele A of the TNF-α-308 gene (TNF-α-308A) is associated with the risk of coronary heart disease [16,17]. The multifunctional proinflammatory cytokine TNF-α influences several risk factors for cardiovascular diseases, in particular, insulin resistance, dyslipidemia, endothelial dysfunction and endothelial activation of cell adhesion molecules [18].…”