Alcohol metabolism is a decisive biological factor that significantly affects alcohol abuse, the development of alcoholism and alcohol damage to organs. The main pathway of ethanol metabolism is the alcohol dehydrogenase pathway to acetaldehyde, which passes into the mitochondria and is oxidized to acetic acid. 80-90% of all ethanol passes through this path. Alcohol oxidase (cytochrome P450), also called microsomal ethanol oxidation system (MEOS/CYP2E1), is responsible for the oxidation of 10-20% of ethanol. The main alcohol metabolizing enzymes exhibit genetic polymorphism and ethnic variation. This review presents recent advances in understanding the functional polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and their metabolic, physiological, and clinical correlations.

Background. Sporadic retinoblastoma develops as a result of de novo mutations in both alleles of the RB1 gene. Often in sporadic retinoblastoma, the initial mutation in RB1 is mosaic, that is, it is formed in a postzygotic, early embryonic cell, which leads to an uneven distribution of mutant clones between different tissues of the body. The ability to identify a mosaic variant of a mutation in the RB1 gene is important for both medical genetic counseling and clinical management of patients, since mosaicism affects the development of the clinical picture of the disease, the risk of developing a tumor in the other eye, as well as other tumors, and the risk of mutation transmission to the next generation. Aim: to establish the frequency and spectrum of somatic mosaic mutations in the RB1 gene in patients with sporadic retinoblastoma and to quantify the content of the mutant allele in cases with mosaicism. Methods. The study was carried out on the DNA of blood lymphocytes from patients with sporadic retinoblastoma. Screening of point mutations, small insertions/deletions in the RB1 gene was performed by semiconductor high-throughput parallel sequencing (NGS). Exclusion of gross deletions in the RB1 gene was performed by MLPA. To search for mosaic mutations with a very low representation (less than 10%) of the mutant allele, an in-depth analysis of the NGS data was developed an in-house algorithm based on bioinformatic and statistical approaches. To verify mosaic pathogenic mutations identified with NGS, Sanger sequencing was used. Results. Mosaic mutations were found more common among patients with sporadic unilateral form of retinoblastoma than in those with sporadic bilateral form; the differences are statistically significant. At the same time, the frequencies of mosaic mutations with a high and low representation of mutant alleles between the groups of patients with unilateral and bilateral retinoblastoma did not differ significantly. All mosaic mutations are null alleles; mosaic missense mutations were not found in our patients’ cohort. No mosaic mutations were detected in the 1st and 2nd exons of the RB1 gene, located proximal to the alternative promoter, the imprinting of which determines the penetrance of mutations depending on the parental origin of the mutant allele. Conclusion. The use of deep high-throughput parallel sequencing in combination with an improved algorithm for analyzing the NGS results, aimed at identifying mosaic mutations, increases the efficiency of DNA diagnostics of retinoblastoma, contributing to the improvement of medical genetic counseling and treatment of patients.

The use of whole-genome sequencing technology provides extensive opportunities for the detection of new genetic markers that determine athletic performance. The aim of the study was to characterize the genome profile of high-class athletes and to identify genetic variants associated with some functional variables which can affect sports success. Materials and methods. For the first time, whole-genome sequencing of 20 professional belt wrestlers of Tatar nationality was carried out. Genetic variants were validated using microarray technology and/or imputation procedure. From the entire spectrum of variants those that were annotated as nonsense mutations, were found at the homozygous state and showed association with muscle mass, lower-extremity peak power, reaction time, and sprinting abilities were selected. The mutant allele frequencies of these variants were compared with the frequencies in other populations of the Volga-Ural region. Results. About 11 million polymorphic loci were found in the genomes of wrestlers, an average of 3.62 million single nucleotide polymorphisms and 617 thousand indels per genome. Of these, 347 variants potentially cause premature termination of protein translation. Correlation with sports phenotypes was found for 6 nonsense mutations (ANKDD1B, SLC6A18, CCHCR1, VOPP1, ADAMTS12, and ZACN genes), which in a homozygous state lead to significant changes in functional indicators of athletes. Wrestlers with p.Tyr319* (rs7447815) substitution in the SLC6A18 gene had decreased relative lower-extremity peak power. At the same time, a lower mutant allele frequency at this locus was registered in Tatar wrestlers compared to the Bashkirs and Russians. Also, according to the GWAS, the rs7447815 substitution is associated with the risk of osteoarthritis and decreased physical activity. Conclusions. The number of polymorphic variants found in the genomes of athletes and the proportion of nonsense mutations in them correlate with the results described for other populations. The nonsense mutation p.Tyr319* (rs7447815) in the SLC6A18 gene is a potential marker that reduces the relative peak power of the lower extremities.

Cardiovascular diseases in alcohol abusers are associated with elevation of plasma levels of proinflammatory cytokines such as IL6, IL8 and CCL2 as well as molecules involved in endothelial functioning including VEGFA, ICAM1 and EDN1. This phenomenon is supposed to be genetically determined. However to date the issue has not been investigated. Thus, we aimed to study the relationship between carriage of SNPs of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) genes with the serum levels of their products and the development of cardiovascular diseases in alcohol abusers. The study included alcohol abusers without apparent somatic pathology and alcohol abusers with clinical manifestations of cardiovascular disease. Serum levels of IL6, IL8, CCL2, VEGFA, ICAM1 and EDN1 were estimated by EIA. SNPs were determined by means of real-time PCR. We found that among the SNPs studied only carriers of homozygous GG genotype and G allele of IL6 (rs1800795) were more frequent in alcohol abusers with cardiovascular diseases. Moreover, carriage of homozygous GG genotype of IL6 (rs1800795) increases the probability of development of cardiovascular pathology in alcohol abusers. However, adjustment for age, gender and the presence of liver cirrhosis, hypertension and diabetes mellitus as co-variates eliminates the enhanced risk of cardiovascular pathology. Polymorphisms of IL6 (rs1800795), IL8 (rs4073), CCL2 (rs1024611), VEGFA (rs699947 and rs2010963), ICAM1 (rs281437) and EDN1 (rs1800541) did not determine serum levels of the related polypeptides.

The main risk factor for the acute non-biliary pancreatitis is alcohol abuse. Alcohol initiates exocrine hypersecretion of the pancreas, creates the prerequisites for increasing pressure in the ducts. Enzymes activate proteolytic enzymes and cause autolysis of pancreatic cells. With an excessive accumulation of trypsin in the tissues, the digestion of the tissues of the gland by its own enzymes begins. SPINK1, a pancreatic secretory trypsin inhibitor, prevents premature activation of zymogens. Aim: to determine the contribution of the rs6580502 polymorphism of the SPINK1 gene and alcohol abuse in the development of acute pancreatitis and its complications. DNA samples obtained from 471 unrelated patients with acute non-biliary pancreatitis and 573 unrelated individuals without gastrointestinal diseases. Genotyping was performed using the PCR method with discrimination of alleles using TaqMan probes. The χ2 criterion and the odds ratio (OR) with 95% confidence intervals (CI) were used to assess the associations of alleles and genotypes of genes with the risk of developing the disease. Statistical analysis was carried out using the Statistica 6.0 software (StatSoft, USA). We found an association of the T/T SPINK1 rs6580502 genotype with an increased risk of developing acute non-biliary pancreatitis (corOR (95% CI)= 1.69 (1.22-2.33); p=0,0015R). In carriers of the TT genotype, the risk of developing SNP was increased by such risk factors as the frequency of drinking more than 2 times per week (corOR (95% CI)= 1,66(1,08-2,57); p=0,02R) and the volume of alcohol consumption more than 200 grams per week (corOR (95% CI)= 6,04(1,81-20,17); p= 0,001R). An association of the T/T genotype with an increased risk of developing edematous pancreatitis was also revealed (corOR (95% CI)= 2.10 (1.44-3.05); Р= 1×10-4 R).

Identification of the etiopathogenesis of the abnormal phenotype in patients with balanced translocations is current trend in cytogenetic laboratories. The formation of developmental anomalies can be associated with the presence of a cryptic genomic imbalance both at breakpoints and on chromosomes not involved in rearrangements.The aim of this study is diagnostics of genomic imbalance in a patient with balanced translocation and abnormal phenotype. The case was characterized by GTG-banding, chromosomal microarray analysis and FISH diagnosis. We present a new case of deletion 8q22.2-q22.3 in child with balanced translocation t(1;6) and developmental delay/congenital defects due to deletion.