[The levels of certain circulating microRNAs in hypertrophic cardiomyopathy are associated with echocardiographic parameters].

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease; it is characterized by left ventricular (LV) hypertrophy that cannot be explained by hemodynamic causes. It is believed that sarcomere dysfunction underlies the pathogenesis of this disease, however, only half of patients with the HCM phenotype have mutations in sarcomere-encoding genes. HCM is distinguished by both high genetic and clinical heterogeneity and therefore more studies are seeking to investigate a regulation of gene expression in HCM and how the abnormalities in this process can affect disease phenotype. One of the levels of regulation of gene expression - a post-transcriptional level - is mediated by short non-coding microRNAs that inhibit protein synthesis. AIM: To identify the correlations between levels of circulating microRNAs, previously shown to be associated with HCM, and clinical parameters of HCM patients. MATERIALS AND METHODS: Correlation analysis of miR-499a-5p, miR-454 and miR-339-5p plasma levels and clinical parameters of 33 HCM patients, examined from 2019 to 2021, has been performed. RESULTS: Variants in HCM-associated genes were found in 49% of patients. There were no clinical differences between genotype-positive and genotype-negative patients. MiR-499a-5p level correlated with LV ejection fraction, miR-454 level - with LV diastolic function parameters and miR-339-5p level - with left atrium dimension. CONCLUSION: Levels of certain circulating microRNAs correlate with echocardiographic parameters in HCM patients.

[Expression analysis of miRNAs from the DLK1-DIO3 locus in CD4+ and CD14+ cells in patients with relapsing-remitting multiple sclerosis]. / Analiz ekspressii mikroRNK iz lokusa DLK1-DIO3 v CD4+ i CD14+ kletkakh pri remittiruyushchem rasseyannom skleroze.

OBJECTIVE: To analyze the expression of several previously unstudied miRNAs from the DLK1-DIO3 locus in peripheral blood mononuclear cells (PBMC) and in CD14+ and CD4+ cell subpopulations in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy individuals. MATERIAL AND METHODS: MiRNA expression analysis was performed in PBMC, CD14+, and CD4+ cells of 14 patients who did not take immunomodulatory drugs, and 14 individuals without autoimmune and inflammatory diseases by reverse transcription followed by real-time PCR. RESULTS: Expression levels of 10 miRNAs selected based on different criteria were significantly higher in PBMC in men with RRMS compared to healthy men; in women, their expression did not change in a similar comparison. No mass unidirectional changes in the expression of these miRNAs in RRMS men were observed in CD14+ and CD4+ cells. High consistency in the expression of miRNA pairs was also not found. CONCLUSIONS: The analysis of PBMC showed the involvement of 10 more miRNAs encoded by genes from the DLK1-DIO3 locus in the development of RRMS. The main observed effect of the increase in the expression levels of these miRNAs in men with RRMS compared with healthy men is not achieved due to the contribution of CD14+ and CD4+ cells. This opens up possibilities for studying the involvement of miRNAs in other PBMC subpopulations in the pathological processes in RRMS.

[MiRNA miR-375 as a Multifunctional Regulator of the Cardiovascular System].

MicroRNA (miRNA) miR-375 acts as a multifunctional regulator of the activity of many physiological and pathological cellular processes by interacting with a large number of target genes. MiR-375 is involved in the regulation of the differentiation and functioning of cells of the nervous and immune systems, bone and adipose tissue, and even the life cycle of a number of viruses. Changes in miR-375 expression have been found in carcinogenesis, inflammation, and autoimmune and cardiovascular diseases. Every year, new studies appear that expand our understanding of the range of processes regulated by this miRNA. According to the latest data, miR-375 can be used as a biomarker and therapeutic target in some diseases. This review discusses the role of miR-375 in the functioning of the cardiovascular system in health and disease.

[Risk of Multiple Sclerosis: Analysis of Interactions Between Variants of Nuclear and Mitochondrial Genomes].

There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each often polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339)*A + MT-ATP6 (rs193303045)*G combination was characterized by p-value = 0.015 and OR= 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358)*G + MT-ND1 (rs1599988)*С combination - by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339*A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01-1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.

[Hypertrophic Cardiomyopathy as an Oligogenic Disease: Transcriptomic Arguments].

Hypertrophic cardiomyopathy (HCM) is the most common genetically determined heart pathology and is often accompanied by fatal complications. Today, the traditional view of the monogenic origin of HCM is being replaced by the idea of it as an oligogenic disease, the clinical phenotype of which is determined not only by mutations in the genes encoding sarcomere proteins in cardiomyocytes, but also by the contribution of other genes (other sarcomeric genes, non-sarcomeric protein-coding modifier genes, and regulatory non-coding RNA genes). Transcriptome analysis is an informative approach for elucidating the nature of HCM, which allows one to evaluate the expression of all genes, evaluate the effect of mutations in a gene on its transcript level, and reveal the mechanisms involved in the regulation of gene expression. This review presents an analysis of published data on the spectra of genes whose differential expression has been detected in the myocardium during the development of HCM in humans and model animals. Special attention is paid to the genes of non-coding regulatory RNAs: miRNAs and long non-coding RNAs, which may be involved in the pathogenesis of the disease. We analyzed studies devoted to the investigation of miRNA levels in the blood of HCM patients to explore the available diagnostic and prognostic biomarkers of the disease. The totality of the reviewed data, despite their relative scarcity, indicates the effectiveness of transcriptome profiling in studying the molecular mechanisms of HCM pathogenesis.

[The Role of microRNA in the Development of Ischemic Heart Disease].

Coronary artery disease is the most clinically significant manifestation of atherosclerosis and the main cause of morbidity and mortality around the world. Atherogenesis is a complex process, involving various types of cells and regulatory molecules. MicroRNA molecules were discovered at the end of the 20th century, and nowadays are the important regulators of several pathophysiological processes of atherogenesis. The review examines data on the participation of various microRNAs in the development of atherosclerosis and its main clinical manifestations and discusses the possibility of using microRNAs as diagnostic markers for these diseases.

Loading Rate of Exogenous and Autoantigenic Determinants on Major Histocompatibility Complex Class II Mediates Resistance to Multiple Sclerosis.

Genetic analysis of thousands of patients with multiple sclerosis (MS) and healthy Russian donors showed that the carriage of groups of HLA-DRB1*15 and HLA-DRB1*03 alleles is associated with the risk of MS, whereas the carriage of groups of HLA-DRB1*01 and HLA-DRB1*11 alleles is protective. Recombinant HLA-DRB1*01:01 with a high affinity can recognize the fragments of myelin basic protein (MBP), one of the autoantigens in MS. However, the comparison of the kinetic parameters of the load of MBP and viral HA peptides on HLA-DRB1*01:01, which is catalyzed by HLA-DM, showed a significantly lower rate of exchange of CLIP for MBP peptides. We assume that the observed protective properties of the group of HLA-DRB1*01 alleles may be directly associated with the ability of HLA-DRB1*01:01 to kinetically distinguish peptides of exogenous and endogenous nature.

[Variability of the MIR196A2 Gene as a Risk Factor in Primary-Progressive Multiple Sclerosis Development].

Multiple sclerosis is a chronic disease of the central nervous system, combining in its pathogenesis both autoimmune and neurodegenerative components, and is characterized by a highly heterogeneous clinical phenotype. Genetic susceptibility to the development of the most common relapsing-remitting course of the disease is extensively studied, while the genetic architecture of the aggressive primary progressive course of multiple sclerosis remains poorly understood. We analyzed the association of polymorphic variants in miRNA genes MIR146A, MIR196A2, and MIR499A with the risk of primary progressive multiple sclerosis one by one and in biallelic combinations with variants of immune-related genes; the analysis was performed in comparison with healthy individuals and with relapsing-remitting multiple sclerosis patients. The allele MIR196A2*C was useful in discriminating between two main courses of multiple sclerosis, one by one and in combination with alleles of the IFNAR2, IL7RA, IL6, PVT1, CD86, CCL5, and PSMB9 genes. The data presented in the current work may be used for the construction of a biomarker panel, to differentiate primary progressive and relapsing-remitting courses of multiple sclerosis on the initial stages of the disease.

[Full - transcriptome analysis of miRNA expression in mononuclear cells in patients with acute decompensation of chronic heart failure of various etiologies].

It is known that micro RNAs are an important regulatory element in the pathogenesis of many diseases, including cardiovascular diseases. Different levels of expression of these molecules in various pathologies makes miRNA a potential diagnostic and prognostic biomarker. AIM: Analysis of miRNA expression levels in mononuclear blood cells (MBC) of patients with acute decompensation f chronic heart failure (CHF) of various etiologies and evaluation of the possibility of their use as a biological marker. MATERIALS AND METHODS: 7 male patients with acute decompensation of CHF with a reduced ejection fraction (EF), NYHA functional class II-IV (FC) according to NYHA [mean (M) EF 29.2%, standard deviation (SD) 13.27%] in age 38 to 65 years old [median (Me) 58 years]. In 3 patients, heart failure developed as a result of dilated cardiomyopathy (DCMP), in 4 patients - against the background of post - infarction cardiosclerosis of the ischemic nature [group of patients with coronary heart disease (CHD)]. The control group - 5 age - matched (from 41 to 57 years old, Me 49 years old) healthy male volunteers. A complete transcript analysis of miRNA expression in MNCs was performed for all patients and healthy volunteers. RESULTS: Differentially expressed miRNAs were determined in patients with CHF (regardless of etiology) compared with healthy individuals: miR-182, miR-144, miR-183, miR-486-5p, miR-143 (log2FC >1, FDR p - value.

[Polymorphic variants of the immune response genes as risk factors for primary progressive multiple sclerosis]. / Polimorfnye varianty genov immunnogo otveta kak faktory riska razvitiia pervichno-progressiruiushchego rasseiannogo skleroza.

AIM: To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). MATERIAL AND METHODS: This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells. RESULTS AND CONCLUSION: The genotypes of IL-4 (rs2243250)*C/C and CLEC16A (rs6498169)*G/G were associated with PPMS in Russians. The association between the HLA-DRB1*15 and PPMS found out in other populations was confirmed in Russians.

Whole-Genome DNA Methylation Analysis of Peripheral Blood Mononuclear Cells in Multiple Sclerosis Patients with Different Disease Courses.

Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.

MicroRNAs: The Role in Autoimmune Inflammation.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level through base-pairing predominantly with a 3'-untranslated region of target mRNA, followed by mRNA degradation or translational repression. Totally, miRNAs change, through a complex regulatory network, the expression of more than 60% of human genes. MiRNAs are key regulators of the immune response that affect maturation, proliferation, differentiation, and activation of immune cells, as well as antibody secretion and release of inflammatory mediators. Disruption of this regulation may lead to the development of various pathological conditions, including autoimmune inflammation. This review summarizes the data on biogenesis and the mechanisms of miRNA action. We discuss the role of miRNAs in the development and the action of the immune system, as well as in the development of an autoimmune inflammatory response. Special attention is given to the role of miRNAs in the autoimmune inflammation in multiple sclerosis, which is a serious socially significant disease of the central nervous system. Currently, a lot of research is focused on this problem.

GWAS-identified multiple sclerosis risk loci involved in immune response: validation in Russians.

Multiple sclerosis (MS) is a chronic neuro-inflammatory disease of complex etiology. The results of GWAS, a high-throughput method to discover genetic architecture of MS, require replication in independent ethnic groups. We performed a replication study of nine GWAS-identified SNPs in immune response in Russians. Associations of CLEC16A and IL2RA with MS were validated. Besides, we observed the associations of CLEC16A and IRF8 in women, and IL7RA and CD58 in men. With multi-locus association analysis two protective biallelic combinations: (TNFRSF1A*T+CLEC16A*A) and (TNFRSF1A*T+IRF8*A) were identified in women. Associations of CLEC16A*G/G and both biallelic combinations in women with MS survived the permutation test.