Excessive alcohol consumption is an etiologic factor in the development of alcoholic liver disease (alcoholic steatohepatitis, alcoholic liver cirrhosis), as well as a risk factor for exacerbations of a number of liver and gastrointestinal diseases, both acquired (hepatitis, viral liver cirrhosis, pancreatitis, etc.) and genetically determined (Gilbert’s syndrome, liver damage in alpha-1-antitrypsin deficiency, cystic fibrosis, etc.). The main pathway of ethanol metabolism in the human body is the oxidative pathway of alcohol dehydrogenase and aldehyde dehydrogenase. The genes encoding the enzymes of this pathway have significant polymorphism, which leads to different degrees of enzyme activity both among individuals and among entire ethnic groups. The review is devoted to modern research and current ideas about the metabolism of ethyl alcohol and nucleotide variants that can affect it. 

Among myodystrophies that debut in early childhood and require early diagnosis and treatment, progressive Duchenne/Becker muscular dystrophy (DMD/BMD, OMIM: 310200) remains the most common and severe form in male patients. The most promising method of modern diagnostics as the second stage of genetic screening of patients with suspected DMD/BMD is clinical exome sequencing. This approach makes it possible to identify pathogenic and likely pathogenic variants not only in the DMD gene, but also in genes associated with other forms of neuromuscular diseases.

The aim of this study was to evaluate the use of clinical exome sequencing as the second stage of genetic screening of patients with suspected progressive Duchenne/Becker muscular dystrophy or other forms of NMD in the Northwestern region of the Russian Federation. The main inclusion criteria were: a previously established clinical diagnosis of DMD/BMD, as well as a significant increase in the level of creatine phosphokinase (creatine kinase, CPK) (>1000U/L), transaminases (according to age-referenced values) – alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In the first stage of the study, patients with a presumptive diagnosis of DMD/BMD were tested for the presence of extended deletions and duplications in the DMD gene using the multiplex ligase chain reaction method. In a second step, patients in whom deletions and duplications were not detected were sequenced for the “clinical” exome by NGS, which includes 3332 genes. A total of 167 patients were examined, with a mean age of 7±2 years. Pathogenic and likely pathogenic variants in the DMD gene, as well as in genes associated with other forms of inherited neuromuscular diseases described previously in RF patients, were identified in 114 patients (68.3%) in our cohort. In 11 patients (6.6%), variants in genes that are not included in the existing RF noncommercial NGS panels for the diagnosis of DMD/BMD and other types of muscular dystrophies were detected, which emphasizes the importance of exome sequencing in patients with a presumptive diagnosis of DMD/BMD for differential diagnosis.

Introduction. Globally, about 64 million people have been reported to suffer from heart failure, and there with increasing the proportion of heart failure with preserved ejection fraction. GNB3 gene encoding β3 subunit of G-protein may be one of the candidate genes for pharmacogenetic approaches to heart failure management.

Aim: to evaluate the frequency of various polymorphisms of the guanine nucleotide-binding protein subunit 3 gene and their role in the development of diastolic dysfunction.

Methods. A cross-sectional study enrolled 87 late postmenopausal women. All patients underwent transthoracic echocardiography, serum the levels of adrenomedullin, renin, NT-proBNP, total cholesterol, low-density lipoprotein, and glucose were assessed. Polymorphisms of the guanine nucleotide-binding protein subunit 3 gene 825 C > T (rs5443) were evaluated by polymerase chain reaction.

Results. The analysis showed that the C allele presence increased the risks of atherosclerotic changes by predisposing to elevated LDL levels and obesity. Although remodeling analysis showed no statistically significant differences between the three possible genotypes, the C allele predisposes more to dilated changes, and the T allele might increase the likelihood of left ventricular myocardial hypertrophy. There were no statistical differences between groups with and without left ventricular diastolic dysfunction and between patients with different levels of adrenomedullin, renin, NT-proBNP.

Conclusions. The revealed interrelationships of polymorphisms and propensity to cardiovascular conditions can contribute to the development of personalized approach to the diagnosis and treatment of patients with heart failure. Absence of differences in patients with the studied genotypes in relation to the levels of neurohumoral factors may be related to adequate long-term treatment with renin-angiotensin-aldosterone system blockers, which decrease negative remodeling effects and changes in the levels of the studied serological markers.

Introduction. Alveolar rhabdomyosarcoma (ARMS) is commonly associated with characteristic fusion transcripts and, in some cases, with oncogene amplifications, including CDK4.

Objective: to determine the prevalence of CDK4 amplification in a cohort of ARMS cases and to evaluate its association with translocation status.

Methods. A retrospective study of 155 formalin-fixed paraffin-embedded tumor samples was performed. CDK4 copy number was assessed by interphase FISH; fusion transcripts were identified by RT-PCR and RNA sequencing. Statistical analysis included calculation of proportions with 95% Clopper-Pearson CIs and χ² tests for comparisons; p<0.05 considered significant.

Results. CDK4 amplification was detected in 22.6% (35/155) of samples. Amplification patterns included low-level (1.5–4 copies), high-level (>4 copies) and clustered signals. Frequencies by translocation subgroup were: PAX3::FOXO1 — 24.7% (25/101), PAX7::FOXO1 — 18.8% (3/16), PAX3::NCOA1 — 25% (1/4), fusion-negative — 17.6% (6/34). No statistically significant associations were found between CDK4 status and clinicopathologic or molecular parameters (p>0.05).

Conclusion. CDK4 amplification is a relatively common genomic event in ARMS; its clinical utility requires further molecular and functional validation.

Background. Coronary atherosclerosis, driven by inflammation, remains a leading cause of mortality. Interleukin-6 (IL-6) is a key proinflammatory cytokine. The rs1800795 polymorphism of the IL6 gene may influence IL-6 levels; however, data on its association with atherosclerosis are conflicting, particularly for the Russian population.

Objective: to comprehensively assess the association of the gene IL6 rs1800795 polymorphism and plasma IL-6 levels with the presence and severity of coronary atherosclerosis in patients from the Russian population.

Methods. The study included 476 patients undergoing coronary angiography. Groups were formed: with atherosclerosis (stenosis ≥50%, n=384) and without (n=92). The rs1800795 polymorphism was genotyped using real-time PCR, and IL-6 levels were determined by enzyme-linked immunosorbent assay (ELISA). Atherosclerosis severity was assessed by the number of affected arteries and the GensiniScore.

Results. IL-6 levels were significantly higher in the atherosclerosis group (3.56 vs. 2.08 pg/mL; p=0.008) and were associated with its presence after adjustment for atherosclerosis risk factors and statin use (OR=4.26; 95% CI: 1.22–14.81). IL-6 concentration significantly increased with a greater number of affected arteries (p=0.02) and showed a weak correlation with the GensiniScore (r=0.15, p=0.04). Carriers of the C/C genotype had significantly lower IL-6 levels (3.76 vs. 5.26 pg/mL, p=0.04). The C/C genotype was associated with a lower likelihood of atherosclerosis in the univariate analysis (OR=0.55; 95% CI: 0.32–0.95) but not after multivariate adjustment (OR=0.57; 95% CI: 0.31–1.05).

Conclusions. Elevated IL-6 level is an independent risk factor for the presence and severity of coronary atherosclerosis. The C/C genotype of rs1800795 is associated with reduced IL-6 levels and demonstrates a trend toward a protective effect; however, this association is not independent of traditional risk factors.

Myosin heavy chain (MyHC) defects cause a variety of hereditary diseases. Phenotypic differences between various entities in this group are associated with patterns of MyHC gene expression (MYH1, MYH2, MYH3, MYH7, MYH8) in muscle cells at different stages of development. Pathogenic variants in the MYH3 gene lead to a more severe syndromic pathology characterized by short stature, scoliosis and joint contractures phenotypes. There are 4 distinctive phenotypes with their own features.

This work presents a patient with short stature, spinal anomalies, large joint contractures and clinical exome sequencing revealed a heterozygous variant c.4956+1G>A in the MYH3 gene. Because the clinical severity of the disease was more consistent with the autosomal recessive form, additional analysis of the noncoding regions of the MYH3 gene was performed, the pathogenic variant c.-9+1G>A was revealed. This example illustrates the importance to include several noncoding regions of the genome with known pathogenic variants in diagnostic panels. Furthermore, a unique feature of the patient we described is the presence of an additional cause of short stature as somatotropic deficiency.

Detection of multilocus imprinting disturbances (MLID) reveals epigenotypes which include data on methylation changes in imprinted genes whose function and contribution to the phenotype have not been well understood yet. The association with the phenotype has not been reliably established for hypomethylation of the GRB10, MEST, and PEG3 genes. The role of MEG8 hypomethylation in the absence of MEG3 hypermethylation in the imprinted cluster on chromosome 14q32.2 is also unclear. Our study of a control cohort of 100 healthy individuals revealed no methylation abnormalities in the GRB10, MEST, and PEG3 genes, likely indicating their involvement in the development of the phenotypes of patients with MLID and other imprinting disorders. However, isolated hypomethylation of the MEG8 gene, detected in 4% of samples, is likely a normal variant.