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The MIC genes are located on chromosome 6 in the class I major histocompatibility complex (MHC) region and encode a membrane-bound stress-inducible protein that acts as a ligand to stimulate the NKG2D activating receptor expressed on the surface of the most natural killer cells (NK). Currently, 7 MIC loci are known, of which only MICA and MICB encode proteins and show a significant allelic polymorphism. The MIC gene polymorphism and their location in the HLA region suggests presence of some ethnic and populational differences for the gene frequencies, linkage disequilibrium of distinct loci, and distribution of HLA-MIC haplotypes, thus making it possible to get information on genetic relationship of human populations. The aim of our study was to assess immunogenetic profile of Russian population in Chelyabinsk Region based on the non-classical HLA loci, i.e., MICA and MICB, in the context of worldwide population data. Methods of the study included immunogenetic typing of 100 donors identifying themselves as Russians, taken from the Registry of Stem Cell Donors at the Chelyabinsk Regional Blood Transfusion Station. The 2 loci (MICA and MICB) were typed at basic resolution, using PCR technique with sequence-specific primers (SSP-PCR). Gene frequencies (GF) were calculated using programs for immunogenetic research (Arlequin 3.5).Among Russian population from Chelyabinsk Region, the following characteristics of the MICA gene distributions were found: MICA *008, *002, *010, *009, frequency of > 7%; average frequencies, for MICA *004, *007, *018, *017; whereas MICA *027, *011, *006, *009:02, *049, *012, *016 was registered at a frequency of < 3.5%. MICB gene profile was as follows: MICB *005:02, *004, *002, *008 at a frequency of > 6%; at a frequency of 4% MICB *003, *005:03; MICB *005:01, * 005:04, * 009N, MICB *013, *014 at a frequency of0.5%. As based on calculated genetic distances (according to Ney) for the MICA locus, the dendrogram and scatter plot were designed by means of multidimensional scaling (MDS) method, presenting location of 30 world populations, including data on Russians in Chelyabinsk Region. The smallest genetic distances between the population of Russians from Chelyabinsk Region and other world populations were found between the population of Slovenia, as well as the USA population of European origin. As based on scatterplot obtained by the MDS approach for MICA gene frequencies, using the data of cluster analysis, we have found that the population of Russians from Chelyabinsk Region belongs to a cluster of typical European populations.The obtained patterns could be used for practical purposes to create a registry of stem cell donors in Russia. In addition, the data may be used as a control group for further research in the area of HLA-disease association, and could be also demanded by the specialists in population ethnogenesis.

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%.

Сomplex intergenic interactions should be taken into account when predicting the risk of adverse course in a pathological process. This presumption is at the heart of evolving multifactorial diseases (ulcerative colitis and irritable bowel syndrome). A single genetic polymorphism seems to be a weak risk factor when predicting the disease evolution and it could not be used as a prognostic model for development of multifactorial pathologies, especially in cases of rare alleles. However, it is well known that the combination of unfavorable alleles of several genes with an additive effect is dangerous. Therefore, identification of such polymorphisms is very important.Previously we conducted a test panel, in order to evaluate associations of alleles and genotypes of some cytokine genes (IL1β, TNFα, IL1rа, IL10, IL6) with predisposal, or resistance for ulcerative colitis and irritable bowel syndrome in the Russian Chelyabinsk region. Distribution of alleles and genotypes of these genes have been assessed in irritation bowel disease (IBD) and ulcerative colitis (UC). The following methods were used: isolation of DNA samples from whole blood, genotyping of the studied gene polymorphisms with PCR, RFLP. A comparative analysis of intergenic interactions between the cytokine genes IL1β, TNFα, IL1ra, IL10, IL6 in the IBD and UC patients was carried out by the Multifactor Dimensionality Reduction method. The analysis is based on the use of polymorphic loci of IL1β, TNFα, IL1ra, IL10, IL6 combinations chosen for analysis of intergenic interactions, with respect to the risk for IBS and UC predisposition. As a result of this study, a fourlocus model IL1β(+3953)*Т/TNFα(-308)*A/IL10(-1082)*G/IL6(-174)*G was identified for IBS, which was characterized by 90% repeatability and prediction accuracy of 74.5%. This model of gene interactions between the cytokine IL1β, TNFα, IL1ra, IL10, IL6 genes had the greatest prediction potential (p < 0.001) in IBS, whereas the model for UC was not statistically significant. The following types of genetic interactions were established: synergism between the IL1β(+3953)*Т and TNFα(-308)*A loci, whereas IL6(-174)*G и IL10(-1082)*G, TNFα(-308)*A seem to be in antagonistic relationships. The study made it possible to establish that the -174G/C IL-6 polymorphism may play a central role and provide intergenic interactions with SNPs of IL1β, TNFα, IL10 for predisposal to irritable bowel syndrome in Chelyabinsk Region of Russia.

Abstract. Common polymorphisms of interleukin-1β, receptor antagonist interleukin-1, and interleukin-4 genes have been studied among the patients with rheumatoid arthritis of Bashkir origin, living in Chelyabinsk Region. As a result of study, an increased frequency of interleukin-1β homozygosity for a high-producer allele was found. An association has been revealed between the homozygosity for 2-repeat allele of interleukin-4, and the age of disease onset.