Background. Studies of comorbid (syntropic) and inversely comorbid (rarely occurring together, i.e., dystropic) diseases have focused on the search for molecular causes of this phenomenon. Materials. We investigated DNA methylation levels in regulatory regions of 23 apoptosis-associated genes as candidate loci associated with the “cancer–neurodegeneration” dystropy in patients with Huntington’s disease (HD) and patients with non–small cell lung cancer (LC). Results. Statistically significant differences in methylation levels between the HD and LC groups were found for 41 CpG sites in 16 genes. The results show that five genes (SETDB1, TWIST1, HDAC1, SP1, and GRIA2) are probably involved in the phenomenon of inverse comorbidity of these diseases. For these genes, the methylation levels of the studied CpG sites were altered in opposite directions in the two groups of patients, compared to the control group. Conclusions. For the SP1 gene, the above hypothesis is supported by our analysis of open-access data on gene expression in patients with the aforementioned diagnoses and fits a probable mechanism of the “HD–LC” dystropy.

Background: Hypertrophic cardiomyopathy is the most frequent autosomal dominant disease, yet due to genetic heterogeneity, incomplete penetrance, and phenotype variability, the prognosis of the disease course in pathogenic variant carriers remains an issue. Identifying common patterns among the effects of different genetic variants is important. Methods: We investigated the cause of familial hypertrophic cardiomyopathy (HCM) in a family with two patients suffering from a particularly severe disease. Searching for the genetic variants in HCM genes was performed using different sequencing methods. Results: A new missense variant, p.Leu714Arg, was identified in exon 19 of the beta-myosin heavy chain gene (MYH7). The mutation was found in a region that encodes the ‘converter domain’ in the globular myosin head. This domain is essential for the conformational change of myosin during ATP cleavage and contraction cycle. Most reports on different mutations in this region describe severe phenotypic consequences. The two patients with the p.Leu714Arg mutation had heart failure early in life and died from HCM complications. Conclusions: This case presents a new likely pathogenic variant in MYH7 and supports the hypothesis that myosin converter mutations constitute a subclass of HCM mutations with a poor prognosis for the patient.

The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest to-gether. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analyti-cal review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The re-view uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is con-sidered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, "second diseases", syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic archi-tecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician's interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions.

Cancer and neurodegenerative disorders present overwhelming challenges for healthcare worldwide. Epidemiological studies showed a decrease in cancer rates in patients with neurodegenerative disorders, including the Huntington disease (HD). Apoptosis is one of the most important processes for both cancer and neurodegeneration. We suggest that genes closely connected with apoptosis and associated with HD may affect carcinogenesis. We applied reconstruction and analysis of gene networks associated with HD and apoptosis and identified potentially important genes for inverse comorbidity of cancer and HD. The top 10 high-priority candidate genes included APOE, PSEN1, INS, IL6, SQSTM1, SP1, HTT, LEP, HSPA4, and BDNF. Functional analysis of these genes was carried out using gene ontology and KEGG pathways. By exploring genome-wide association study results, we identified genes associated with neurodegenerative and oncological disorders, as well as their endophenotypes and risk factors. We used publicly available datasets of HD and breast and prostate cancers to analyze the expression of the identified genes. Functional modules of these genes were characterized according to disease-specific tissues. This integrative approach revealed that these genes predominantly exert similar functions in different tissues. Apoptosis along with lipid metabolism dysregulation and cell homeostasis maintenance in the response to environmental stimulus and drugs are likely key processes in inverse comorbidity of cancer in patients with HD. Overall, the identified genes represent the promising targets for studying molecular relations of cancer and HD.

The genetic structure of susceptibility to cardiovascular disease continuum (CVDC) comorbidity was analyzed, and the functional importance of the genetic variants associated with the pathology was assessed. The association with CVDC was demonstrated for the rs1333049 (CDKN2B-AS1), rs3739998 (KIAA1462), rs3765124 (ADAMDEC1), and rs1007856 (ITGB5) polymorphisms that formed the genetic structure of susceptibility to CHD complicated by MI, regardless of the presence/absence of risk factors. The rs626750 (MMP3/MMP12), rs1991401 (DDX5), rs2878771 (AQP2), and rs2277698 (TIMP2) polymorphisms were associated with coronary heart disease (CHD) and MI depending on the presence of risk factors (AH, HC, and T2DM). The association with MI without comorbidities was demonstrated for rs3739998 (KIAA1462), rs1991401 (DDX5), and rs2878771 (AQP2); with MI + AH, for rs1333049 (CDKN2B-AS1), rs3765124 (ADAMDEC1), and rs1007856 (ITGB5); with MI + AH + HC, for rs1333049 (CDKN2B-AS1), rs3765124 (ADAMDEC1), rs1007856 (ITGB5), and rs626750 (MMP3/MMP12); and the association with "CVDC syntropy" was found for rs3739998 (KIAA1462) and rs2277698 (TIMP2). All SNPs associated with CVDC were cis-eQTL loci and affected gene expression in tissues of CVDC target organs or changed the transcription factor affinity as a result of the binding site loss or gain.

Objective. To assess the association of single nucleotide polymorphisms of genes potentially involved in the comorbidity of bronchial asthma (BA) and essential hypertension (HTN) in patients with different time onset of the diseases.Design and methods. Genotyping of 92 SNPs was performed using MALDI-TOF mass spectrometry in patients with BA and HTN (n = 97) and healthy individuals (n = 153). The group of patients with comorbid pathology was divided into two subgroups depending on the time of onset of symptoms of BA relative to HTN, and the prevalence of all studied SNPs was compared in each subgroup relative to the control.Results. The variant rs11590807 regulating expression for UTP25, TRAF3IP3, C1orf74, HSD11B1-AS 1, IRF6 genes in the heart, blood vessels, and lung is associated with BA and HTN, regardless of the time onset of each of these diseases. Associations of other variants are specific with respect for each subgroup of comorbid diseases. The rs1010461 variant, which regulates the expression of RNASE4 and ANG genes, is linked with HTN as the first phenotype of the comorbidity. The rs769214, rs11032700, rs11032699, rs484214, and rs480575 variants, which regulate the expression of CAT gene, are associated with BA as the first phenotype of disease comorbidity.Conclusions. We found specific associations of the studied polymorphic variants in the development of comorbid phenotypes of BA and HTN, which differ in the time of manifestation of each of the diseases relative to each other.

The phenomenon of comorbidity between monogenic and multifactorial diseases suggests the involvement of a certain common number of genes and biological pathways in the formation of the predisposition to diseases, known as the Mendelian code, which links each multifactorial disease with a unique set of Mendelian loci. Within the omnigenic model of multifactorial diseases, genes of Mendelian diseases can be represented by core genes that function in the cells of the target organs of the pathology and participate in their pathogenesis. Mendelian diseases can be used as a starting point for prioritizing loci/genes related to complex traits and diseases. This approach was applied in this review by the example of prioritizing genes in loci associated with hypertrophic and dilated cardiomyopathies as a result of genome-wide association studies. The functional characteristics of the Mendelian disease genes in the genetic structure of the susceptibility to multifactorial diseases will provide new knowledge about core and peripheral genes and their areas of competence. It is important to analyze the Mendelian code of multifactorial diseases using the multiomic approach, which will allow one to identify driver genes and biological pathways associated with the development of diseases.

Background Recent studies have focused on the potential role of epicardial adipose tissue (EAT) in the development of coronary artery disease (CAD). ABCA1 and ABCG1 transporters regulate cell cholesterol content and reverse cholesterol transport. We aimed to determine whether DNA methylation and mRNA levels of the ABCA1 and ABCG1 genes in EAT and subcutaneous adipose tissue (SAT) were associated with CAD. Methods Paired EAT and SAT samples were collected from 82 patients undergoing elective cardiac surgery either for coronary artery bypass grafting (CAD group, N = 66) or valve surgery (NCAD group, N = 16). ABCA1 and ABCG1 mRNA levels in EAT and SAT samples were analyzed using real time polymerase chain reaction, ABCA1 protein levels in EAT samples were assessed by western blotting. ABCA1 and ABCG1 DNA methylation analysis was performed in 24 samples from the CAD group and 9 samples from the NCAD group via pyrosequencing. Results DNA methylation levels in the ABCA1 promoter and ABCG1 cg27243685 and cg06500161 CpG sites were higher in EAT samples from patients with CAD compared with NCAD (21.92% vs 10.81%, p = 0.003; 71.51% vs 68.42%, p = 0.024; 46.11% vs 37.79%, p = 0.016, respectively). In patients with CAD, ABCA1 and ABCG1 DNA methylation levels were higher in EAT than in SAT samples (p < 0.05). ABCA1 mRNA levels in EAT samples were reduced in the subgroup of patients with CAD and concomitant carotid artery disease or peripheral artery disease compared with the NCAD group (p = 0.024). ABCA1 protein levels in EAT samples tended to be lower in CAD patients than in the NCAD group (p = 0.053). DNA methylation levels at the ABCG1 cg27243685 site positively correlated with plasma triglyceride concentration (r = 0.510, p = 0.008), body mass index (r = 0.556, p = 0.013) and waist-to-hip ratio (r = 0.504, p = 0.012) in SAT samples. Conclusion CAD is associated with ABCA1 and ABCG1 DNA hypermethylation in EAT. CAD with concomitant carotid artery disease or peripheral artery disease is accompanied by decreased ABCA1 gene expression in EAT. DNA methylation levels at the ABCG1 cg27243685 locus in SAT are associated with hypertriglyceridemia and obesity.

Markers of eosinophilic inflammation were studied in bronchial asthma patients and their relatives (bronchial hyperreactivity, eosinophils of nasal smear, total serum immunoglobulin E, interleukin-5). An association of C-703T interleukin-5 gene polymorphism and the disease was analysed. Results of our study showed a close relationship between eosinophils in nasal smear, total serum immunoglobulin E and bronchial hyperreactivity in mechanisms involved in asthma and atopy development. The statistically significant association of C-703T interleukin-5 gene polymorphism with asthma was shown.

An attempt was made to discover pathogenic links between gene polymorphism of interleukin-4 which is critical inflammatory cytokine, atopic features, respiratory function and bronchial hyperresponsiveness (BHR) in 70 families of atopic asthma patients. Spirometry, methacholine challenge test (MasterLab pro), serum total IgE level, serum IL-4 level (by the ELISA method), skin prick tests (Immuno Tek), IL-4 (-589C /T, G /C З'-utr) and IL-4RA (lleSOVal, Glu551Arg) genes polymorphism were investigated in 70 probands (11.6 ± 1.2 yrs) and 247 relatives (36.7 ± 1.2 yrs) from Tomsk region (Siberia). Significant associations of certain variants of polymorphous IL-4 and IL-4RA genes with bronchial airflow param eters (FEVt), atopic features (increased IgE level), and bronchial asthma severity were found. Patients with persistent mild, moderate, and severe asthma had their proper variations of polymorphism. The methacholine challenge test was an objective marker of BHR in this study but any associations between BHR and IL-4 and IL-4RA polymorphous variants were not found.

Болезнь Гентингтона (БГ) - нейродегенеративное заболевание, причиной которого является экспансия числа CAG-повторов в первом экзоне гена HTT. Превышение порога в 36 повторов приводит к БГ. Диапазон от 27 до 35 CAG-повторов составляют так называемые промежуточные аллели, которые, согласно последним данным, модифицируют клинические проявления нейродегенеративных заболеваний. В данном исследовании выявлено два случая носительства промежуточных аллелей с 27 CAG- повторами у пациентов с болезнью Паркинсона (БП). Анализ клинической картины выявил «нетипичность» клинического проявления БП. Таким образом, промежуточные аллели гена HTT оказывают модифицирующее влияние на течение БП. Huntington’s disease (HD) is a neurodegenerative disease, caused by a CAG-repeat expansion in exon 1 of the HTT gene. The number of repeats more than 36 leads to HD. The range of 27-35 CAG-repeats is called as intermediate alleles (IAs). There is a growing evidence of importance of IAs for patients with other neurodegenerative diseases. In this study we have detected two cases of carriage of IAs in patients with Parkinson’s disease (PD). The analysis of clinical picture has revealed atypical clinical features of PD in these individuals. Thus, IAs of HTT gene may provide a modifying effect on clinical features of PD.

Проведен сравнительный анализ генетической структуры предрасположенности к прогрессированию фиброза печени при хроническом вирусном гепатите С (ХВГС) и алкогольной болезни печени (АБП). С циррозом печени при ХВГС ассоциирован генотип СС rs708272 гена CETP (OR=4,08 [95%CI:1,69-10,03]; р=0,001). С алкогольным циррозом ассоциирован генотип CG rs12054703 гена NUP155 (OR=1,86 [95%CI:1,11-3,13]; р=0,016). Генотип CG rs7590760 гена DNMT3A является протективным относительно развития алкогольного цирроза (OR=0,43 [95%CI:0,24-0,78]; р=0,004). Таким образом, выявлено, что генетическая компонента предрасположенности к циррозу печени различна для этиологически разных форм заболевания. We performed the comparative analysis of the genetic structure of a predisposition to the progression of liver fibrosis in HCV-related infections and alcoholic liver disease. Genotype СС rs708272 of CETP gene was associated with cirrhosis in HCV-infected patients (OR=4,08[95%CI:1,69-10,03]; р=0,001). Genotype CG rs12054703 of NUP155 gene was associated with alcoholic liver cirrhosis (OR=1,86[95%CI:1,11-3,13]; р=0,016). Genotype CG rs7590760 of DNMT3A gene had protective effect on the alcoholic liver cirrhosis (OR=0,43[95%CI:0,24-0,78]; р=0,004). The genetic structure of a predisposition to liver cirrhosis is different for chronic hepatitis C virus infection and alcohol-induced liver injury.

The goal of the study was to analyze copy number variation (CNV) in the GBP3 gene between white blood cells and atherosclerotic plaques of patients with carotid atherosclerosis. The material was both blood samples and atherosclerotic plaques obtained from the same patients with carotid atherosclerosis ( n = 94). Assessment of CNV was performed using digital droplet PCR. As a result, it was shown that among 94 patients with carotid atherosclerosis, the CNV frequency was 44 % in the GBP3 gene in leukocytes. Deletion was detected in 5 (5.3 %) patients, and loss in 36 (38.3 %) patients. The gain was identified in one patient. Somatic mosaicism was found in 12 (13 %) of patients, comparing DNA samples of atherosclerotic plaque tissue and white blood cells from the same patients. Mosaic copy number losses predominantly were detected in white blood cells, in contrast mosaic copy number gains were identified in atherosclerotic plaques. Somatic mosaicism of the GBP3 gene is widespread in atherosclerosis. Different ratio of mosaic clones carrying certain type of CNV in GBP3 gene is presented.

The study of the phenomenon of a combination of several diseases at the same time in an individual, actualized in the second half of the 19th century, is being actively analyzed 150 years later using genetic approaches. We present an overview of the results of such studies in relation to allergic diseases, in particular, a special variant, the so-called «atopic march», the sequential development of eczema, allergic rhinitis and asthma («atopic march» syntropy). The data of genetic and epidemiological studies were summarized, the analysis of genome-wide associative studies was carried out, and the role of mutations in the filaggrin gene (FLG) in the development of the «atopic march» syntropy was considered.

Background and Aims: MiR-10b plays a significant role in atherosclerotic plaque formation and is regulated by TWIST transcription factor. Inhibition of miR-10b led to development of atherosclerosis-resistant phenotype and stabilized advanced lesions in mice. We analyzed DNA methylation within MIR10B and TWIST1 genes in tissue samples of patients and healthy individuals to assess epigenetic state of these loci in atherosclerosis.