[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.

[DNA Methylation Profile of CD14+ Monocytes Changes in Primary Progressive Multiple Sclerosis].

Multiple sclerosis (MS) is a chronic autoimmune inflammatory and neurodegenerative disease of the central nervous system, which is characterized by significant clinical heterogeneity. Primary progressive MS (PPMS) develops in 10-15% of patients. Unlike the most common relapsing-remitting form of MS, PPMS involves steady progress of neurodegeneration and, as a consequence, a persistent gradual increase in neurological symptoms. The peculiarities of epigenetic regulation of gene expression may be one of the reasons for the differences in the pathogenesis of the two MS forms. DNA methylation is one of the key epigenetic mechanisms, which remains almost unexplored in different cell populations of PPMS patients. The goal of this work was to identify differential methylation profiles of the CpG sites in the CD14+ monocyte DNA, which characterize PPMS. A genome-wide analysis of DNA methylation in PPMS patients and healthy individuals has identified 169 differentially methylated positions (DMPs), 90.5% of which were hypermethylated in PPMS patients. More than half of all DMPs are located in/near known genes and within CpG islands and their neighboring regions, which indicates their high functional significance. We have found six differentially methylated regions (DMRs) in the OR2L13, CAT, LCLAT1, HOXA5, RNF39, and CRTAC1 genes involved in inflammation and neurodegeneration, which indicates active epigenetic regulation of their expression.

[Association of Polymorphic Genome Variants in the 2q32.1 Locus with the Development of Vasovagal Syncope].

The vasovagal syncope (VVS) is the most common form of syncope. The mechanisms of VVS development are not entirely clear. It is known that there is a genetic predisposition to this disease, but the data on the roles of individual genes are quite contradictory. Recently, a genome-wide association study identified a locus at chromosome 2q32.1 associated with a united group of diseases, that is, syncope and collapse; among the single nucleotide polymorphisms (SNPs) of this locus, the most significant association was observed for rs12465214. In a homogeneous sample of patients diagnosed with VVS, we analyzed the association of rs12465214, rs12621296, rs17582219 and rs1344706 located on chromosome 2q32.1 with this form of syncope. In the enrolled set, only rs12621296 was associated with VVS by itself, whereas associations of other SNPs were observed only in biallelic combinations. An epistatic interaction between the components of the combination rs12621296*A + rs17582219*A was revealed. The possible involvement of individual genes on the 2q32.1 locus in the genetic architecture of the VVS is discussed.

[A comparison of DNA methylation profiles of blood mononuclear cells in patients with multiple sclerosis in remission and relapse]. / Sravnenie profilei metilirovaniya DNK mononuklearnykh kletok krovi bol'nykh rasseyannym sklerozom v stadiyakh remissii i obostreniya.

OBJECTIVE: To study the whole-genome DNA methylation profiles of peripheral blood mononuclear blood cells (PBMCs) of patients with relapsing-remitting multiple sclerosis (RRMS) in remission and relapse in order to assess the contribution of this epigenetic mechanism of gene expression regulation to the activity of the pathological process. MATERIAL AND METHODS: Eight patients with RRMS in remission and 6 patients in relapse were included in the study. Methylation levels of DNA CpG sites in PBMCs were analyzed using Infinium HumanMethylation450 BeadChip DNA microarrays. RESULTS: Seven differentially methylated positions (DMPs) were identified, of which 3 were hypermethylated (cg02981003, cg18486102, cg19533582) and 4 were hypomethylated (cg16814680, cg1964802, cg18584440, cg08291996) during RRMS relapse. Five DMPs are located in protein-coding genes (GPR123, FAIM2, BTNL2, ZNF8, ASAP2), one in microRNA gene (MIR548N), and one in an intergenic region. For all identified DMPs, we observed a change in DNA methylation levels of more than 20% (range 20.2-57.5%). Hierarchical clustering of DNA samples on the heatmap shows their clear aggregation into separate clusters corresponding to RRMS patients in the stages of relapse and remission. CONCLUSION: For the first time it was shown that during relapse and remission of RRMS there are differences in the DNA methylation profile that allow discrimination between these clinical stages. These data indicate the involvement of the epigenetic mechanism of DNA methylation in the activation of the pathological process in RRMS.

[Molecular cardiology: from decoding the genetic nature and mechanisms of the diseases development to the introduction into the clinic].

In recent decades, advances in molecular biology have led to a change in understanding the inheritance mechanisms and development of cardiological diseases of predominantly genetic origin, such as hypertrophic and dilated cardiomyopathies, familial hypercholesterolemia, etc. This knowledge made it possible to develop fundamentally new drug interventions. Programs for detecting cardiac diseases of predominantly genetic origin have been created, including genetic counseling and testing. Competence in this area is becoming a necessary part of a cardiologist's job.

[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.

[Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis].

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.

[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.

DNA Methylation As an Epigenetic Mechanism in the Development of Multiple Sclerosis.

The epigenetic mechanisms of gene expression regulation are a group of the key cellular and molecular pathways that lead to inherited alterations in genes' activity without changing their coding sequence. DNA methylation at the C5 position of cytosine in CpG dinucleotides is amongst the central epigenetic mechanisms. Currently, the number of studies that are devoted to the identification of methylation patterns specific to multiple sclerosis (MS), a severe chronic autoimmune disease of the central nervous system, is on a rapid rise. However, the issue of the contribution of DNA methylation to the development of the different clinical phenotypes of this highly heterogeneous disease has only begun to attract the attention of researchers. This review summarizes the data on the molecular mechanisms underlying DNA methylation and the MS risk factors that can affect the DNA methylation profile and, thereby, modulate the expression of the genes involved in the disease's pathogenesis. The focus of our attention is centered on the analysis of the published data on the differential methylation of DNA from various biological samples of MS patients obtained using both the candidate gene approach and high-throughput methods.

[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.

[Radiologically isolated syndrome: prognosis and predictors of conversion to multiple sclerosis]. / Radiologicheski izolirovannyi sindrom: prognoz i prediktory transformatsii v rasseyannyi skleroz.

Increased sensitivity and availability of magnetic resonance imaging (MRI) in neurological routine practice led to the fact that more and more experts began to encounter changes typical for multiple sclerosis (MS) according to MRI in the absence of anamnestic and clinical indications of damage to the central nervous system (CNS). This nosological form has been defined as a radiologically isolated syndrome (RIS). More and more RIS cases convert to MS (up to 30% in the first 5 years after RIS diagnosis). At the moment, there are no biological markers that allow combining RIS and MS into one pathological process and early treatment with disease-modifying drugs (DMT). Prospective studies are actively being conducted to identify demographic, clinical, neuroimaging and biochemical conversion predictors. The identification of the molecular biological RIS features, combining these changes with MS, is an urgent scientific task and will allow timely initiation of therapy of the pathological process already at the subclinical stage.

[Variability of the Mitochondrial Genome and Development of the Primary Progressing form of Multiple Sclerosis].

Recently, it has been shown that dysfunction of mitochondria is an important component of the molecular mechanisms of the development of many neurodegenerative diseases. These include multiple sclerosis, a chronic autoimmune and neurodegenerative disease of the central nervous system, which is characterized by clinical heterogeneity. The role of genetic variability of mitochondrial DNA in the development of various clinical forms of multiple sclerosis is poorly understood. The aim of present study was to analyze the association often mitochondrial DNA single nucleotide polymorphisms and the nine most common European mitochondrial haplogroups (H, J, K, U, T, I, V, W and X) with a severe and relatively rare multiple sclerosis disease form-primary progressive multiple sclerosis. 110 patients with primary progressive multiple sclerosis and 406 healthy controls were enrolled in the study, all ethnic Russians. For the first time association of the m.12308*G (rs2853498) variant (P = 0.024) and haplogroup U (P = 0.0004, passes the adjustment for multiple comparisons: Pcorr = 0.0076) with primary progressive multiple sclerosis was shown. Comparison of these data with the results of our previous study [1], that was focused on the role of mitochondrial genome variability in susceptibility to the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis, leads to the conclusion that two different mitochondrial haplogroups, U and J, are involved in the development of two different clinical forms of multiple sclerosis. The results may contribute to the identification of new targets for the treatment of primary progressive multiple sclerosis, for which there is no effective pathogenetic treatment at the moment.

[Age-Dependent Approach to Search for Genetic Variants Associated with Myocardial Infarction].

Myocardial infarction (MI), one of the most common manifestations of cardiovascular system aging, is often fatal. The vast majority of studies on genetic susceptibility to age-dependent diseases are carried out using the case-control study design. However, its use involves a number of difficulties, most of which arise when establishing the control group of relatively healthy individuals. In this work, survival functions were analyzed for carriers of alternative polymorphic variants of 18 genes that had been tested for association with MI using the case-control approach in our previous study, and the magnitude of the shift in the age of the disease onset depending on individual variations of the genome was estimated. The following risk variants were associated with the age of MI: rs2430561*A of IFNG (HR = 1.3, P = 0.043), rs1799889*5 of PAI-1 (HR = 1.3, P = 0.039), rs1800896*GG of IL10 (HR = 1.5, P = 0.0048), rs1800471*C of TGFB1 (HR = 1.5, P = 0.043), and rs11614913*TT of MIR196A2 (HR = 1.5, P = 0.035). In carriers of these variants, the disease developed 3-6 years earlier than in carriers of alternative variants. The results of this study were compared with data on the associations with MI previously obtained on the same sample using the case-control approach. It turned out that the estimates based on the two methods mostly disagreed. However, the age-dependent approach relies on fewer assumptions that can be additionally verified. In our opinion, it makes this approach more promising than the case-control design.

[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.

[Genetic Markers for Personalized Therapy of Polygenic Diseases: Pharmacogenetics of Multiple Sclerosis].

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.

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.

Involvement of Mitochondria in Neurodegeneration in Multiple Sclerosis.

Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as "neurodegenerative diseases". Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved.