No abstract

Allele typing of single-nucleotide polymorphisms (SNPs) may be used in predictive medicine and to determine targets for the most effective treatment strategies for various diseases. The purpose of the present work was to investigate the association between the SNPs of inflammatory genes, e.g., IL10 (C819T; rs1800871; C592A; rs1800872); IL4 (C589T; rs2243250); fibrosis-related factors - TGFβ1 (G915C; rs1800471); MMP1 (1607insG; rs1799750); apoptosis-regulators (TNFRSF11B G1181C; rs2073618); vasoconstricting factors (CRP C3872T; rs1205); CYP1A1 (A2454G; rs1048943), endothelial dysfunction (EDN1 G925T; rs5370); (NOS3 C786T; rs2070744) and development of coronary heart disorders, breast cancer, bronchial asthma (BA) and threatened miscarriage in early pregnancy among population of the Republic of Adygea.DNA samples of unrelated donors and patients (n = 74) with verified diagnoses of bronchial asthma (n = 13), coronary heart disease (n = 10), breast cancer (n = 10) and threatened miscarriage in the first trimester of pregnancy (n = 8) were isolated from peripheral blood leukocytes and typed by allele-specific polymerase chain reaction with electrophoretic detection of results using commercial tests-systems of NPF “Litech”, Moscow.The study in a group of Adygea residents has revealed the statistical significance for the “normal” Arg25-allelic variant of the TGFβ1 gene (p < 0.05; F = 0.038; OR = 3.231; 95% CI = 1.081-9.656) in the development of bronchial asthma. There were no significant differences in SNP rs1800471 of the TGFβ1 gene in the groups with cardiovascular, oncological diseases and gestational disorders (p > 0.05). The frequency distribution of allelic variants NOS3 C786T; TNFRSF11B G1181C; 1607insG of the MMP1 gene; G925T of the EDN1 gene, and CYP1A1 2454G in the examined patients with cardiovascular disease and breast cancer did not significantly differ from the control group (p > 0.05). The statistical significance for the frequency of allelic variants rs1799750 (MMP1 gene) in cases of threatened early miscarriage and in women with a physiological course of pregnancy (F = 0.096; p < 0.05%: OR = 6.0) was close to reliable, but with a confidence interval > 1.0 (95% CI = 0,98036,716), thus requiring further research.The obtained data could be sufficient in order to suggest predisposition for bronchial asthma, as well as to develop a set of preventive measures taking into account the individual characteristics of each patient.

Understanding the pathogenetic mechanism of development and identifying trigger markers of the disease will significantly increase the efficiency of pre-nosological diagnosis and medical follow-up of patients. In this case, one should take into account the role of mutations in cytokine genes, which affect their biochemical activity and production level. The objective of the study was to investigate the role of mediators of acute and chronic inflammation (IL-17A, IL-1â, TNFá and IL-4), the ratio of natural killer cell subpopulations (CD56hiCD16-/CD56loCD16+) in pathogenesis of coronary atherosclerosis resulting into coronary heart disease.To analyze the results, an integrated approach was used, including molecular genetic methods such as polymerase chain reaction, typing of single-nucleotide substitutions in cytokine genes, isolation and cultivation of peripheral blood mononuclear cells, assessment of spontaneous and in vitro-induced production of immune system mediators, enzyme-linked immunosorbent assay, cytotoxic test, flow cytometry with monoclonal antibodies (Beckman Coulter, USA) to CD16, CD56 NK markers.The study included 130 residents of the North Caucasus, including the patients (n = 62) treated at the Cardiology Department of the Adyghe Republican Clinical Hospital (ARCB) with a verified diagnosis of ischemic heart disease (IHD), and a control group (n = 68), represented by unrelated healthy donors.Overexpression of cytokines in IHD patients was associated with distinct single nucleotide substitutions in certain genes. Studying a group of residents from the Republic of Adygeya, the authors experimentally established that harboring the 511C allele of the IL-1â gene (p < 0.0004; OR = 4.67), A197A of the IL-17A gene genotype (p < 0.04; OR = 3.88), G308 SNP of TNFá gene (p < 0.01; OR = 3.41), and 589T variant of IL-4 gene (p < 0.04; OR = 2.45) are associated with hyperproduction of the first-wave inflammatory mediators that increase the risk of developing ischemic heart disease. In atherosclerosis and associated cardiovascular diseases, we have noted a significant decrease in spontaneous and induced activity of natural killer cells involved in the utilization of “foamy cells”. The NK activity of peripheral blood mononuclear cell in patients with coronary heart disease is significantly reduced. In the IHD patients, an imbalance of phenotypically and functionally different CD56hiCD16-/CD56loCD16+ NK subpopulations with a predominance of CD56hiCD16- phenotype were revealed. Conclusions: Immuno-inflammatory mechanisms of evolving coronary atherosclerosis are associated with single-nucleotide substitutions, i.e., polymorphisms in the promoter regions of the IL-17A (G197A), IL-1 â (T511C), and TNFá (G308A), the known mediators of acute and chronic inflammation.Genetically determined overexpression of IL-17A, IL-1â, and TNFá, confirmed in experiments on evaluation of spontaneous and stimulated cytokine production in patients with CHD, together with reduced NK activity of РВМС, due to predominance of CD56hiCD16-, a subpopulation with high cytokine production, manifested by an increased pro-inflammatory component that triggers and provides long-term support to pathophysiological processes of atherosclerosis.