Медицинская иммунология (Aug 2020)
Combinations of proinflammatory cytokine genes and their interactions in Russian tuberculosis patients in the Chelyabinsk Region
Abstract
Tuberculosis is a widespread infectious disease caused by M. tuberculosis, which is one of the leading causes of death in the world. According to numerous literature data, this is a genetically determined disease, and genetical polymorphism is a mechanism that leads to progression from infection to clinical manifestation. Susceptibility to infection correlates with different genes at several loci, and each individual gene plays a unique role. It is known, that the analysis of individual polymorphic variants of genes does not provide a sufficiently complete picture of the mechanisms of formation of a predisposition to multifactorial pathologies, such as tuberculosis, since their development is based on complex intergenic and gene-environmental interactions, which must be taken into account when predicting the risk of developing active forms of the disease and its severity. The concept of the functioning of cytokines as biomarkers of tuberculosis suggests that their products and interactions play an important role in the immunopathogenesis of the disease, because they form a cytokine chain with unique functions, where the removal of any link in the chain disrupts the entire mechanism of the immuno-inflammatory process. IL-6, together with TNFα and IL-1β, initiate early pro-inflammatory reactions in tuberculosis, stimulating local and systemic inflammatory reactions under participation of all common pro-inflammatory mechanisms with further transition to activation of acquired immunity. Earlier, we carried out a set of studies to evaluate the association of alleles and genotypes of these cytokine genes with a predisposition/resistance to pulmonary tuberculosis in Russians of the Chelyabinsk region. These studies have resulted into assessment of certain distribution patterns of IL-1β, TNFα, IL-6 alleles and their genotypes in pulmonary tuberculosis and its various clinical forms. The following methods were used: isolation of DNA samples from whole blood, genotyping of the studied gene polymorphisms using PCR and RFLP techniques. In this study, we analyzed the intergenic interactions of the genes for the pro-inflammatory cytokines IL-1β, TNFα, IL-6 using the method of reducing multifactor dimension in patients with pulmonary tuberculosis. The program designs optimal models of combinations for the studied genes and their interactions in tuberculosis patients. As a result of this study, a three-locus model IL-6 (-174)*С – IL-1β (+3953)*Т – IL-1β (+3953)*С was established, which was characterized by 100% reproducibility and prediction accuracy of 72%. Among the analyzed polymorphisms, the IL-6 (-174)*C polymorphism possessed the highest predictive potential with 15.27%.
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