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The levels of spontaneous and concanavalin A-induced production of some key cytokines (TNF-α, IL-1β, IL-4, Il-6, and IL-10) were assessed in the cultures of mononuclear cells derived from healthy volunteers examined for polymorphism of the promotor sites of the respective genes. The presence of certain allelic variants in the promoter regions of human cytokine genes mostly determines the rates of induced and spontaneous cytokine production. Allelic variant -31C of IL-1β gene is associated with high production rate of the related cytokine. In addition, polymorphism of allelic variant C-590T of IL-4 gene significantly affects the production rates of IL-1β, TNF-α, IL-6, and IL-10.

Aim: To analyze the association of the promoter polymorphism of the genes of the matrix metalloproteinases (MMP) MMP2 (-1306), MMP3 (-1171), and MMP9 (-1562) and two vascular endothelial growth factor (VEGF) gene regulatory regions (-2578, +936) with the development of myocardial infarction (MI)., Materials and Methods: DNA was analyzed in 251 patients with a history of MI. Five polymorphic positions were genotyped by restrictase analysis of amplification products, by using specific primers., Results: In addition to the MMP3 5A5A monogenotype, there were 4 complex genotypes that were significantly different between two analyzed groups and positively associated with acute coronary syndrome. Among them, each of two genotypes included 2 polymorphic positions; two genotypes did 3 analyzed polymorphic positions. Four complex (two-locus (n = 1), three-locus (n = 2), four-locus (n = 1) genotypes that were negatively associated with MI were also identified., Conclusion: These findings are evidence in favor of our assumption that the increasing number of genotypes as part of the analyzed combined genetic complexes detectable in one patient considerably enhances the clinical significance of the results of immunogenetic analysis.

Objective: To study frequencies of occurrence of the combined genetic attributes including different variants of cytokines genotypes (TNFA, IL1B, IL4, IL6, IL10, VEGF), in different on sexual and age groups in population of Siberia Caucasoid., Material and Methods: Frequencies of distribution of variants of structure genes cytokines networks among 500 representatives of Siberia Caucasian population, men and women of two age groups--more younger than 35 years ("young") and 55 and more years ("elderly") are investigated. In structure of investigated genes cytokines net has come 10 variants of polymorphic sites of cytokines genes and vascular endothelial growth factor gene: TNFA-863 C --> A, TNFA-308 G --> A, TNFA-238 G --> A, IL1B-31 C --> T, IL4-590 C --> T, IL6-174 G --> C, IL10-1082 G --> A, IL10-592 A --> C, VEGF-2578 C --> A and VEGF+936 C --> T. Genotyping are carried out by restriction fragment length polymorphism method. Processing of results carried out on the basis of the original methodological approach including the complex connected computer analysis of genic circuits of various dimension., Results and Conclusions: It is shown, that the significant part of variants genes cytokines networks, which widely distributed among young people is completely absent in the "elderly" age group. Such variants disappearing with age separately for men and women are established. At the program mathematical analysis it is established, that parameters of the odds ratio achieve two-place sizes (OR = 27, p = 0,0004), that testifies to high specificity of complex genetic attributes. Presence in genome such variants of genes cytokines networks, found out in the childhood or young age, as supposed, is unfavorable personalized prognostic factors of life span of the individual.

Cytokines as regulators of activity of inflammation play significant role in mechanisms of formation of atherosclerotic plaques and in processes of their destabilization. One of leading genetic factors determining level of their production appears to be polymorphism of cytokine genes structure at their promoter loci. We have conducted an analysis of distribution in groups of healthy male and female survivors of myocardial infarction (MI) of combined genetic signs represented as a complex of genotypes of a number of studied cytokine genes : TNF-A863C; TNF-A308G; TNF-A238G; IL1B-C511T; IL1B-C-31T; IL4-C590T; IL6-C174G; IL10A-1082G IL10-A592C. Among these homozygous combinations of cytokine genotypes characterizing a group of men who have lived up to middle and old age without development of MI there are widely represented genotypes associated with high levels of production of both cytokines with pronounced proinflammatory (IL-1) and antiinflammatory (IL-4, IL-10) activity. Absence of such multidirectional combinations in genome of patients with myocardial infarction can be considered one of genetic factors of risk of development of acute distirbances of coronary circulation.

Aim: To study the distribution of genotypes in the cytokine genes and their combinations with immunoregulatory activity in patients with type 2 diabetes mellitus (T2DM) and in healthy women., Subjects and Methods: 586 Europeoid women from the eastern regions of Russia, including 374 healthy women aged 23-68 years and 212 women aged 28-69 years with T2DM complicated and uncomplicated by osteoporosis, were examined. Seven polymorphisms located in the promoter regions of the interleukin (IL) gene: TNF-alpha at positions C-863A, G-308A, G-238A, IL1B T-31C, IL6 G-174C, IL10 C-592A, VEGFA C-2578A were investigated. Restriction analysis of amplification products was applied., Results: There were high associations of the predisposition and resistance to the development of T2DM with a number of polylocus cytokine genotype combinations having pro- and anti-inflammatory, angiogenic, and immunoregulatory activities. The association of the cytokine genes with T2DM was found to be mediated in nature through a relationship of the genotypes to the high or low production of regulatory cytokines and to different factors of regulation of lipid and carbohydrate metabolisms, inflammation, and bone remodeling., Conclusion: The high odds ratio and high specificity of the detected genetic combinations allow one to hope that they will be clinically used as predictors.

The article reports results of the first study of cytokine gene polymorphic sites and analysis of distribution of their complexes among healthy subjects and patients with rheumatoid arthritis (RA) representative of the Russian Europeoid population; their possible prognostic significance is evaluated. Comprehensive analysis of the frequency of allelic variants of cytokine genes IL1B C-31T, IL6 G-174C, TNFA A-238G, TNFA A-308G, TNFA A-863C, IL4 C-590T, IL10 A-592C and VEGF C-2578A was performed for 513 residents of the Novosibirsk region showing no obvious signs of any diseases and 125 RA patients. The results suggest association of RA with certain alleles of pro- and anti-inflammatory cytokine genes. Complex indices reflecting combinations of genotypes of two, three, four, five, six and seven loci of the explored cytokine genes found in individual patient demonstrate their high specificity for RA. It is supposed that these findings can be used in further clinical studies for the development of algorithm designed to detect risk groups among clinically healthy subjects.

Aim: To analyze the prognostic value of detection of allelic variants of the promoter regions of cytokine genes in patients with rheumatoid arthritis (RA) with varying efficiency of basic anti-inflammatory therapy (BAIT)., Subjects and Methods: Eighty-nine patients with a valid diagnosis of RA, of them there were 79 females and 10 males (mean age 52.5 +/- 13.1 years), were examined. The patients received BAIT with methotrexate in a dose of 10.0-17.5 mg/week (77.5%) or with sulfasalazine in a dose of 2.0 g/day (22.5%) for 24 weeks. The efficiency of BAIT was evaluated using the European League Against Rheumatism (EULAR) criteria (DAS28) following 24 weeks. A high therapeutic effect was stated when DAS28 decreased by more than 1.2 scores. Changes in DAS28 by less than 0.6 scores were regarded as ineffective BAIT. Cytokine gene polymorphisms were studied by restriction analysis of amplification products. The following polymorphic sites in the interleukin genes: FNOA at positions C-863A, G-308A, G-238A, IL-1BT-31C, IL-4 C-590T, IL-6 G-174C, and IL-10 C-592A, were explored., Results: The IL-6 G-174G genotype associated with the high production of this proinflammatory cytokine and the IL-IB C-31C genotype associated with the low production of interleukin-1beta (IL-1beta) were most frequently encountered in a group of patients with the high efficiency of BAIT (22 and 24.7%). At the same time the C allele associated with the low production of IL-6 and the IL1B T-31C genotype associated with the high production of this cytokine were most frequently detected at position of G-174C of the promoter regions in the IL-6 gene in patients unresponsive to BAIT (32 and 36%)., Conclusion: The allelic variants of the promoter regions of the IL-6 G-174G, IL-1B C-31C, IL-4 C-590T, and IL-10 C-592A can be genetically prognostic factors of formation of the high efficiency of BAIT.

Aim: To study HLA associations with HP-positive duodenal ulcer (DU)., Material and Methods: A total of 47 Europeoid DU and 680 healthy subjects were examined for class I and II HLA antigens. Typing of class I antigens was conducted in the microlymphocytotoxicity test, of class 2 antigens--by polymerase chain reaction., Results: The study has found associations of duodenal ulcer with HLA-A10, -B41 and different combinations of these alleles whereas HLA-A9 was protective. A relative risk of peptic ulcer was 3.03 in HLA-A10 (pcor < 0.05) and 7.78 in HLA-B41 (p < 0.001). The allele A9 occurred more frequently in healthy controls (30.15%) than in Helicobacter pylori-positive patients with DU (10.64%, RR = 3.50, pcor < 0.05). Frequencies of alleles HLA-DR7 and HLA-A1/B12 were higher in HP-positive DU patients with family history of peptic ulcer (RR = 4.00 and RR = 11.92, respectively, p < 0.05)., Conclusion: These data suggest that HLA may influence duodenal ulcer susceptibility and resistance. The relationships help prognosticate not only development of the disease in HP infection but also the age of the infection manifestation.

The results of DNA typing of the HLA-DPB1 gene among Tuvinians are described. The allele 0201 was found to be the most frequent (26.66%); then, in order of decreasing frequency, followed the alleles 0401 (26.42%), 0402 (13.99%), 0301 (8.55%), 0501 (7.77%), 0901 (5.16%), and 1301 (2.07%). The frequency of the allele 0501 in Tuvinians was significantly lower than that in the published data on allele distributions characteristic of two other Mongoloid populations, the Manchu and Japanese. The results of the serological typing of the loci HLA-A, -B, and -Cw of class I in the Tuva population were compared to the corresponding published data on ten Mongoloid populations of Central and Eastern Asia: Uigurs, Kazakhs, Mongols, Manchu, Tibetans, the Chinese of the northern and southern regions of China, Thais (inhabitants of Northwestern Indochina), Koreans, and Japanese. In Tuvinians, the most frequent antigens were HLA-A2, -A9, -B0, -B35, -B17, -Cw4, and -DR5. In the inhabitants of Tuva, the frequency of the antigens HLA-A1, -A9, -B17, -Cw2, and -Cw4 was significantly higher than in other Mongoloids, while that of the antigens HLA-A26 and -B22 was lower. This difference was greatest in the case of antigen HLA-B40: it a frequency of 43.4% was detected in it, while in individuals of Mongolian origin, the frequency of this antigen did not exceed 22.5%. Indices of genetic similarity (IGSs), calculated from the gene frequencies of the loci HLA-A, -B, and -Cw, suggested that the Tuvinians were most closely related to Kazakhs (IGS = 0.73), and least related to the Japanese and Uigurs (IGS = 0.66). Our data suggest that Tuvinians significantly differ from the compared populations of Central and Eastern Asia.

An immunogenetic examination of 86 cases of stomach cancer established a correlation between predisposition and resistance, on the one hand, and the distribution of allele sets of HLA-genes (classes I and II), on the other. The relationship was found to vary according to sex and age. The most significant relationships with respect to predisposition were identified for HLA-B51 (RR = 19.82) alleles and allele combinations of HLA-DRI-DR7 (RR = 25.52) and HLA-A9-DRI (RR = 33.67). High relative risk of stomach cancer was attributed to the absence of relevant alleles in 91 patients included into the group of comparison. Also, combinations of allele sets were identified in healthy subjects which never occur in stomach cancer patients. The results provide a substantiation for developing an automated system of interpreting HLA-typing data which are instrumental in evaluating the patient's predisposition, resistance and prognosis.

To develop some individual prognostic criteria of SLE clinical course the Wald's analysis of immunogenetic markers (HLA) was used. The obtained summarized diagnostic coefficients allow predicting a subacute or chronic pattern of the disease, the rate of generalization and the most frequent location of the process in certain organs. The constant character of HLA-typing results and the simplicity of the given prognostic tables made the proposed diagnostic method convenient for medical practice.

HLA typing data of two little populations living in Tajmyr peninsula (Dolgans and Nganasans) and Chukotka peninsula (Chukchas and Chuvantses) were presented. Our data were compared with the International standard distribution of class I HLA antigens in orients and its distribution in orients who live in the Asian part of Russia. Indexes of genetic distribution and genetic likeness were calculated.

HLA antigens distribution among subgroups of rheumatoid arthritis (RA) patients was compared with reference to the results achieved after the treatment with transfusion of extracorporeally irradiated autologous blood (TEIB). The treatment efficacy was found to be in general 66% and to depend on HLA phenotype, age of the patients, the RA activity. The analysis of associations of clinical significance exhibited by clinical, laboratory and immunogenetic signs made it possible to derive a formula for individual prognostic criterion capable of raising TEIB efficacy to 89%.

Examination of 166 patients with optic neuritis revealed that 65 of them developed multiple sclerosis (MS) at different times after optic neuritis. The observation period was 9.4 years on the average. Using the clinical, laboratory, immunogenetic methods the clinico-immunogenetic heterogeneity of optic neuritis was discovered, the highly informative specific clinical signs and immunogenetic markers suitable as criteria for predicting different variants of optic neuritis outcomes were defined. Using a heterogeneous successive procedure a method of individual ++pre-nosological prediction of MS in persons with a history of optic neuritis was devised.

Distribution of HLA antigens, haplotypes and phenotypes of the histocompatibility complex was studied and compared in 110 patients with tick borne encephalitis, living in Novosibirsk. The disease patterns and varieties were many and varied. Distribution of HLA antigens in 140 healthy subjects also living in Novosibirsk served as control. Based on the results of the immunogenetic examination of patients with tick borne encephalitis, the methods were elaborated, enabling one to predict with a high accuracy of probability the development of the feverish, meningeal or focal forms of tick borne encephalitis, one- or two-wave disease variety within the first days of disease. Concurrent analysis of the sex of the person bitten by the virulent tick and combination in one genotype of several allelic forms of the main histocompatibility complex genes allows one to raise appreciably the prognostic significance of the immunogenetic examination and to elaborate high-informative individual diagnostic criteria.

An increase in the level of soluble HLA-A and B antigens in the blood serum of patients with rheumatoid arthritis and systemic lupus erythematosus was observed using IKO-1 monoclonal antibodies and polyspecific alloantisera. This increase was accompanied by the elevation of the concentration of beta 2-microglobulin (the light chain of the molecules of HLA-antigens of the 1st class). A degree of the concentration of soluble HLA-antigens and beta 2-microglobulin depended on a degree of disease activity, a variant of a clinical course and the presence of visceral involvement.

The authors calculated sensitivity, specificity, informativeness and diagnostic coefficient and relative risk of the joint index reflecting the degree of T-lymphocytes activation in patients with RA as compared with healthy persons and patients in the control group.

The immune and endocrine systems and HLA genotype were subjected to a comparative study in patients with systemic and discoid lupus erythematosus (SLE, DLE). The patients suffering from these diseases were found to differ in a number of the parameters of the immune status including the content in blood serum and supernatant of the cultivated mononuclear cells of the soluble molecules HLA-A, HLA-B and HLA-DR. The degree of the SLE and DLE association with the genes and haplotypes of class I HLA complex was different as was the character of the association of HLA-A and HLA-B specificities with the activity of the immune system cells and with hydrocortisone content in plasma. The common immunogenetic syndrome characteristic of SLE and DLE patients has been identified.

HLA antigens were compared in groups of patients with disseminated sclerosis and healthy donors. In remission group as compared with controls, increased were the rates of A9, B7, B13, B35, A0/B17, A1/B7, A9/B7, A3/B35, A11/B7, A11/B8, B5, B7, 15, and in the progredient group--B7, Bw22, B35, A1/B7, A2/B7, A2/B35, A9/B7, B7, 12. These groups were different only in A11/B7 rates. Remitting and progredient course of the disease in women differed in A3 and A10 rates, in men in A2 and A11. In men with remitting course the A2 antigen rate was substantially lower than in any other group. With respect to the disease duration and the degree of patients's invalidization, the groups of benign, malignant, and intermediate course were singled out differing from each other and controls also in their HLA composition.

The contents of class 1 HLA antigens was compared in patients with disseminated sclerosis, their first-grade relatives and healthy donors. Patients, as compared to healthy persons, had higher occurrence rate of A1, A9, B7, A0/B0, A9/B7, A1/B7, A1/B12, A2/B7, B7, 27, B5, 0, B7, 12, B7, 15, B5, 7, and lower A28, B13, Bw22, B35, 40, B7, 35, A2, w19, A0/B35, A0/B13, A2/B15, A3/B35. In male patients, as compared to female patients, B40 and A1/B15 were more frequent, and B12 less frequent. The subgroup of patients with the diseases onset before 20 years considerably differed from other patients in their rates of A1, A1, 2, A1w19, A1/B0 increased and A3 and A9/B17 decreased. Compared to donor group, the patients' relatives had differences similar to those between patients and relatives. High relative risk values were characteristic of some of the above associations.