Aortic aneurysm (AA) is a life-threatening condition, and aortic rupture that is the complication of AA in the absence of emergency surgery leads to death. Genetic (more often in thoracic AA—TAA) and environmental factors (in TAA and abdominal AA—AAA) contribute to the development of AA. This review summarizes the data of scientific publications devoted to the study of DNA methylation under the influence of AA risk factors, as well as in the cells of different parts of the aorta (thoracic, abdominal) in normal and pathological conditions. Changes in DNA methylation are observed in aortic and/or blood cells in the presence of AA risk factors (arterial hypertension, smoking, age, and comorbidities). Studies of DNA methylation in TAA and AAA are few and have been conducted using different approaches to sample formation, cell sample selection, and experimental methods. However, they provide convincing evidence of the altered DNA methylation status of genes selected for study using a candidate approach (in the AAA study), as well as of different genomic regions in genome-wide DNA methylation analysis (mainly in TAA studies). Genes localized in differentially methylated regions are associated with the functioning of the cardiovascular system and are involved in cellular and metabolic processes pathogenetically significant for the development of AA. In a number of cases, the association of DNA methylation levels with clinical parameters in AA has been established. These results indicate the prospect of expanding the studies of DNA methylation in AA, including the identification of new pathogenetically significant links in AA development.

The aim of the present study was to summarize the data on the spectrum of genetic diseases and their phenotypic manifestations in case of structural and functional defects in 75 genes, pathogenic variants of which are associated with the formation of different types of cardiomyopathy (CMP). The search for scientific publications was carried out in foreign (PubMed) and Russian (eLibrary) digital libraries. The data analysis was performed using the Simple ClinVar, An Online Catalog of Human Genes and Genetic Disorders, and STRING databases.It was shown that the vast majority of CMP genes are pleiotropic. Monogenic diseases caused by mutations in CMP genes are characterized by a wide range of pathological manifestations in various organs and systems (cardiovascular, nervous, endocrine, musculoskeletal systems, connective tissue, skin and appendages, organs of vision and hearing, kidneys) as well as by metabolic and immune disorders. Therefore, if a patient (regardless of the primary diagnosis) has pathogenic / likely pathogenic variants or variants of uncertain significance in the CMP genes, we recommend a detailed and comprehensive clinical examination. This is important for clarifying the effects of rare genetic variants, identifying significant clinical and prognostic features for CMP and monogenic diseases associated with CMP genes, and identifying risk groups and controllable triggers that contribute to the manifestation of pathogenic genetic variants.

The review analyses the scope of the genes of Mendelian cardiomyopathies (CM), specifically hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathy. According to Simple ClinVar, pathogenic/likely pathogenic variants of 75 genes trigger one or more types of CM. At the same time, these genes are characterized by their expression in various tissues and organs (not only in the heart and blood vessels but also in various parts of the brain, gastrointestinal tract, etc.), as well as by their involvement in a variety of metabolic pathways and biological processes. These data are generally consistent with the results of genome-wide association studies (GWAS). Polymorphisms of the CM genes are associated with various types of CM and other cardiovascular diseases, as well as obesity, various diseases of the musculoskeletal and nervous systems, and mental, oncological, infectious, and other diseases. In addition to pathological conditions, common variants of the CM genes contributed to the variation of a wide range of quantitative traits, including pathogenetically significant for various multifactorial diseases. The non-randomness of the identified associations of CM genes with a wide range of diseases is evidenced by comorbidity of CM with GWAS-associated diseases or the involvement of the latter as a symptom, a risk factor for the development of myocardial pathology, and a modifier of the clinical presentation; overlapping of the affected organ systems and the spectrum of pathologies associated with common variants (according to GWAS) and to which rare pathogenic variants (according to OMIM) of the CM genes lead; and confirmation of the involvement of CM genes in the pathogenesis of diseases of other organ systems at the molecular level. Thus, the data presented in the review indicate the wide scope of the genes of primary CMs, which goes beyond the cardiovascular system. That indicates the relevance of conducting comprehensive studies aimed at determining the cause-and-effect relationships between the CM and pathological conditions of other organs, including with the involvement of molecular genetic data.

A broad range of SNP markers associated with diseases and pathogenically significant features were identified in noncoding regions of the human genome. The mechanisms that underlie their associations are a pressing problem. A number of associations was previously observed between polymorphic variants of DNA repair proteins genes and common diseases. To clarify the possible mechanisms of the associations, a detailed annotation of the regulatory potential of the markers was carried out using online resources (GTX-Portal, VannoPortal, Ensemble, RegulomeDB, Polympact, UCSC, GnomAD, ENCODE, GeneHancer, EpiMap Epigenomics 2021, HaploReg, GWAS4D, JASPAR, ORegAnno, DisGeNet, and OMIM). The review characterizes the regulatory potential for the polymorphisms rs560191 (of the TP53BP1 gene), rs1805800, rs709816 (NBN), rs473297 (MRE11), rs189037, rs1801516 (ATM), rs1799977 (MLH1), rs1805321 (PMS2), and rs20579 (LIG1). General characteristics of the markers are considered, and data are summarized to describe their influence on expression of their own and co-regulated genes and binding affinity of transcription factors. The review additionally considers the data on adaptogenic and pathogenic potentials of the SNPs and co-localized histone modifications. A possible involvement in regulating the functions of both their own and nearby genes may explain the associations of the SNPs with diseases and their clinical phenotypes.

Cardiomyopathies are an actively investigated clinically and genetically heterogeneous group of myocardial pathologies. At present, it is acknowledged that along with genetic factors, epigenetic mechanisms can be of high value in determining both the risk of this pathology and the formation of clinical features of the disease. This review provides an analysis of studies examining histone modifications and chromatin remodeling, as well as alterations in DNA methylation in different forms of cardiomyopathies. Most of the studies in this field are focused on the analysis of the epigenomic profile of myocardial specimens from patients with dilated cardiomyopathy. The development of cardiomyopathy (dilated, hypertrophic, ischemic, restrictive, and arrhythmogenic) is accompanied by changes in the myocardium at the level of epigenetic processes, which leads to alterations in gene expression and an imbalance of metabolic pathways, including those pathogenetically important for the development of heart diseases. Cardiomyopathy genes ( LMNA , TNNI3 , ANKRD1 , SLC25A4 , EYA4 , GATAD1 , PRDM16 , and DMD ) are also involved in epigenetic alterations occurring in the myocardium. Epigenetic modifications, as well as enzymes that regulate epigenetic processes, are analyzed in terms of the prospects for their use to identify new molecular markers and metabolic pathways that are of value for cardiomyopathies, to develop diagnostic panels and new drugs. At the same time, high clinical and etiological heterogeneity of cardiomyopathies, a large number of diverse and interrelated epigenetic processes that occur both in physiologically normal state and in the disease pathogenesis point to the need to expand epigenetic studies in different forms of cardiomyopathies, including the level of epigenome, transcriptome, and epitranscriptome using omics approaches for the measurements of individual myocardial cells in humans and model animals, as well as in cell lines, in disease modeling.

The review summarizes the current knowledge on the role that genetic factors play in primary or Mendelian cardiomyopathies (CMs) and certain secondary CM forms. Dozens of genes with pathogenic or likely pathogenic variants were described for primary CMs. The spectrum of causal genetic variants is specific to particular CMs in most cases, but common genes and variants were also discovered. Genetic causes of the disease remain unknown in part of primary CM cases, and pathogenic variants of Mendelian disease genes are found in secondary CMs as well. The genetic component in the development of both primary and secondary CMPs was additionally established in genome-wide association studies (GWASs). Single nucleotide polymorphisms (SNPs) associated with primary and secondary CMs are, in most cases, specific to different CM types and contribute little to an individual’s overall risk. Certain SNPs were associated with electrocardiogram or echocardiogram features of the morphologically normal heart in humans. Most of the CMs-associated SNPs are in noncoding genome regions, but have a regulatory potential, acting as loci that affect the level of expression (eQTLs), splicing (sQTLs) or epigenetic modifications in the heart. It is noteworthy that the effects of eQTL and sQTL genotypes are not equivalent in different anatomical regions of the heart in some cases. The phenotype and clinical presentation of CMs in general can be determined by a wide range of rare pathogenic or likely pathogenic variants with a strong effect and common polymorphisms with a small effect and modified by epigenetic factors.

Noncoding RNAs (ncRNAs) play an important regulatory role in the activity of genes essential for the development and functioning of cardiovascular system. Intragenic ncRNAs are coordinately regulated and/or expressed with their host genes, including ncRNAs the genes of which are located in the regions of cardiomyopathy (CMP) related genes. This review summarizes the results from studies analyzing the involvement of intragenic ncRNAs in the functioning of the heart in normal conditions and during the development of CMPs of different origin. The intragenic CMP-associated ncRNAs most actively recruited to the study are microRNAs (miR-1, miR-133a, miR-208a, miR-208b, miR-324, miR-490, miR-499a), as well as long ncRNAs (MHRT, TTN-AS1, and KCNQ1OT1). It was demonstrated that the levels of these ncRNAs in the myocardium were dynamically regulated in ontogeny, depending on gender and the heart’s anatomical part. Expression of these ncRNAs in the myocardium/blood serum in humans and animal models is changed under the influence of exogenous and endogenous factors, demonstrating an association with clinical features during the CMP development and progression. The change in the ncRNA levels preceding clinical manifestation of the disease, the reported possibility of arresting the development of CMP, and even the restoration of normal phenotype by controlling the levels of these regulatory molecules point to their involvement in the pathogenesis of the disease. MicroRNAs and long ncRNAs, the genes of which overlap in location with the CMP related genes, participate in different metabolic processes that are important for normal functioning of the heart, including the involvement in epigenetic processes.

The status of DNA methylation in the human genome changes during the pathogenesis of common diseases and acts as a predictor of life expectancy. Therefore, it is of interest to investigate the methylation level of regulatory regions of genes responsible for general biological processes that are potentially significant for the development of age-associated diseases. Among them there are genes encoding proteins of DNA repair system, which are characterized by pleiotropic effects. Here, results of the targeted methylation analysis of two regions of the human genome (the promoter of the MLH1 gene and the enhancer near the ATM gene) in different tissues of patients with carotid atherosclerosis are present. Analysis of the methylation profiles of studied genes in various tissues of the same individuals demonstrated marked differences between leukocytes and tissues of the vascular wall. Differences in methylation levels between normal and atherosclerotic tissues of the carotid arteries were revealed only for two studied CpG sites (chr11:108089866 and chr11:108090020, GRCh37/hg19 assembly) in the ATM gene. Based on this, we can assume the involvement of ATM in the development of atherosclerosis. “Overload” of the studied regions with transcription factor binding sites (according to ReMapp2022 data) indicate that the tissue-specific nature of methylation of the regulatory regions of the MLH1 and ATM may be associated with expression levels of these genes in a particular tissue. It has been shown that inter-individual differences in the methylation levels of CpG sites are associated with sufficiently distant nucleotide substitutions.

Heart failure (HF) is a widespread syndrome that leads to a significant decrease in the quality of life of patients. Epigenetics is one of the most promising areas of HF research, which allows us to consider the pathogenesis of this syndrome at a new molecular level. This review summarizes the studies of epigenetic processes (histone modification, DNA methylation, changes in the expression of regulatory non-coding RNAs) that accompany HF development. Epigenetic studies of HF not only confirmed the clinical and etiological heterogeneity of this syndrome, but also expanded the range of potential diagnostic markers and opened up new drug development strategies.

Non-coding RNAs (ncRNAs) play an important role in the regulation of the activity of genes essential for the development and function of the cardiovascular system. Intragenic ncRNAs have been shown to be coordinately regulated and/or expressed with their host genes, including ncRNAs resided within cardiomyopathy (CMP)-related genes. This review summarizes the results of CMP-related intragenic ncRNA studies in the function of the healthy heart and in the development of different forms of CMPs. CMP-related intragenic ncRNAs such as miRNAs (miR-1, miR-133a, miR-208a, miR-208b, miR-324, miR-490, miR-499a) and long ncRNAs (MHRT, TTN-AS1 and KCNQ1OT1) are actively involved in research. It has been established that the level of these of ncRNAs in myocardium is characterized by developmental-stage-specific dynamics, gender-specific and chamber-specific patterns. These ncRNAs exhibit differential expression in myocardium/serum of humans and model animals under the influence of exogenous and endogenous factors. The expression levels of these ncRNAs in the myocardium/serum is associated with clinical features during the development and progression of CMPs. The change in the level of ncRNAs preceding clinical manifestation of CMPs have been reported. The possibility to arrest the development of CMPs and even the restoration of the normal phenotype by controlling the levels of these regulatory molecules indicate their involvement in the pathogenesis of the disease. miRNAs and long ncRNAs, whose genes resided within CMP-related genes, are involved in various metabolic processes that are important for the heart function, including their involvement in epigenetic processes.

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include micro RNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

Xenobiotic metabolism system in the current populations is involved in the biotransformation of a wide range of endogenous substrates and various xenobiotics, which can contribute to developing the diseases of various organ systems, and, in some cases, comorbid conditions where increased biotransformation system activity is observed. In this regard, it is of great interest to study the involvement of polymorphism in xenobiotic metabolism genes in the development of both isolated pathology and various comorbid conditions. Aim . The goal of study was to investigate the involvement of rs4244285 in the CYP2C19 gene in the development of isolated pathology and comorbidities. Material and Methods. The frequencies of alleles and genotypes were studied in groups of patients with comorbid conditions including groups of coronary artery disease (CAD) with hypertension (HTN) (CAD_HTN, n = 133) and bronchial asthma (BA) with HTN (BA_HTN, n = 178), in group of isolated BA ( n = 135), and in the population sample of the city of Tomsk ( n = 377). Association analysis covered three initial groups of patients (CAD, BA, and BA_HTN) and subgroups assigned based on the presence of absence of HTN diagnosis taking into account comorbid conditions both in patient samples and in population control. Results and Discussion. The study demonstrated the predisposing eff ect of GA genotype on the development of comorbid BA and HTN (OR = 1.94, p = 0.038) and comorbid CAD and HTN (OR = 2.26, p = 0.009) compared to isolated BA. The AA genotype was observed 3.98 times less often in HTN patients than in normotensive individuals. However, the diff erences did not reach the level of statistical signifi cance due to the low occurrence of this genotype. Conclusion . The obtained results may be explained by the involvement of CYP2C19 -metabolites of arachidonic acid in the regulation of vascular tone, which requires further study.

Dilated cardiomyopathy (DCM) is one of the most common and clinically heterogeneous forms of cardiomyopathy characterized by a high risk of unfavorable course and outcome. A complex etiology has been shown for DCM. Genetic factors contribute to both familial and sporadic cases. The review summarizes information on the role of genetic factors in the clinical variability of DCM. Much of the data accumulated to date indicates a high genetic heterogeneity of DCM. There are numerous rare pathogenic variants in more than 100 genes that lead to the disease. The type, number, and localization of these genetic variants can affect the clinical course of DCM. Furthermore, common genetic variants are localized in various loci, including genomic regulatory regions and genes of “monogenic forms” of DCM, acting as factors modifying the pathological phenotype.

Хронический вирусный гепатит С (ХВГС) является многофакторным заболеванием со сложной генетической компонентой. В настоящем исследовании была изучена вовлеченность гена PMS2 в развитие ХВГС и прогрессирование фиброза до цирроза печени. Проанализированы частоты аллелей и генотипов rs1805321 в гене PMS2 у пациентов с ХВГС (n=150) и популяционной выборке г. Томска (n=345). Установлена ассоциация изученного маркера с ХВГС: к развитию патологии предрасполагают аллель С (p=0,00005) и генотип СС (p=0,013), генотип TT является протективным (p=0,00002). Показано, что аллель С предрасполагает к развитию цирроза печени (p=0,038). Изученный полиморфный вариант может также влиять на темп прогрессирования фиброза печени при ХВГС. Chronic viral hepatitis C (HCVC) is a multifactorial disease with a complex genetic component. The present study examined the involvement of the PMS2 gene in the development of HCVC and the progression of fibrosis to cirrhosis. The frequencies of alleles and genotypes of rs1805321 in the PMS2 gene were analyzed in patients with chronic hepatitis C (n=150) and in a population samples from the Tomsk (n=345). The association of the studied marker with HCVC was established: the C allele (p=0.00005) and the CC genotype (p=0.013) predispose to the development of pathology, the TT genotype is protective (p=0.00002). Allele C has been shown to predispose to the development of liver cirrhosis (p = 0.038). The studied SNP may also affect the rate of progression of liver fibrosis in HCVC.

The review analyzes variability of clinical manifestations of p.Arg870His in the MYH7 gene, which is repeatedly registered in patients with hypertrophic cardiomyopathy (HCM). The analysis involves the data from scientific publications obtained as a search result in the PubMed, СlinVar, and eLibrary.ru databases, as well as authors’ own results. A wide range of phenotypic manifestations have been revealed in carriers of p.Arg870His, from the asymptomatic to severe course, rapid progression, and early death. The review considers possible factors that modify the effect of the pathogenic variant (i.e. dosage of the pathogenic variant, the presence of other unfavorable genetic variants, etc.). The importance of accumulating information on the clinical features of HCM in the carriers of specific gene variants is emphasized in order to clarify their pathogenicity and to identify factors modifying the clinical outcome, which is important for the choice of the treatment strategy for HCM.

The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include micro RNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

The "Mendelian code" hypothesis postulates a relationship between Mendelian (monogenic) and common pathologies. In this hypothesis, polymorphisms in the genes of Mendelian diseases may have a significant contribution to predisposition to common diseases in which the same biochemical pathways may be involved. In this review a group of genes encoding various proteins participating in the DNA repair, with a particular focus on the BRCA1-associated genome surveillance complex (BASC), is presented through the prism of the "Mendelian code" hypothesis. Here we discuss (1) their main functions in the repair of DNA double-strand breaks (ATM, MRE11, NBN, RAD50, BRCA1, and BLM) and mismatch repair (MSH2, MSH6, MLH1, PMS2, RF-C, and PCNA); (2) the mitochondrial involvement of these proteins; (3) the involvement of BASC proteins in the development of an adaptive immune response. For 13 out of 16 BASC protein encoding genes, mutations leading to monogenic diseases have already been described; for 11, there are associations with common diseases or individual biological processes. Patients with mutations in the genes of the BASC complex and patients with severe combined immunodeficiency share similar symptoms. Polymorphisms within DNA repair genes may play a role in the development of common diseases through the involvement of the immune response. The pleiotropic effects of these genes suggest their participation in the development of various conditions, both in health and pathology.