The use of antipsychotics is associated with elevated prolactin levels. Drug-induced hyperprolactinemia (HP) has not only short-term, but also long-term consequences, which can seriously affect the patient’s quality of life. Clinical manifestations of HP include gynecomastia, galactorrhea, menstrual irregularities, sexual dysfunctions, infertility, as well as a significant increase in the likelihood of developing osteoporosis and cancer. Not only exogenous, but also genetic factors are involved in the development of this side effect of antipsychotic therapy. The aim of this work was to study the clinical and molecular genetic factors of the development of drug-induced HP and the creation of a prognostic model of the risk of developing HP, which in the future can be used to optimize and personalize the prescribed therapy in the treatment of schizophrenia. The study was conducted in populations of russians with schizophrenia (n = 446), living in the West Siberian region of Russia. The average age of patients was 41,5 ± 13,4 years (18 - 65 age range). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression scale (CGI), the side effect rating scale (Udvalg for Kliniske Undersogelser Scale - UKU), and a modified version of the card of a standardized description of patient with schizophrenia. Based on the results on the serum prolactin level patients were divided into subgroups: with HP (n = 227) and with normal prolactin levels (n = 219). Molecular genetic analysis of 88 polymorphic variants of serotonin receptors genes (HTR2C, HTR3A, HTR3B, HTR6, HTR2A, HTR1A, HTR1B) and dopamine receptors genes (DRD1, DRD2, DRD2 / ANKK1, DRD3, DRD4), dopamine transporter gene SLC6A3, noradrenaline transporter gene SLC6A2, genes of the cytochrome P450 enzymes (CYP1A2*1F, CYP2D6*3, CYP2D6*4, CYP2C19*3, CYP2C19*17, CYP2C19*2), gene of catechol-O-methyltransferase COMT, gene of glutathione S-transferase P (GSTP1), genes ATXN1, KREMEN1 and prolactin gene PRL was performed. A prognostic model was obtained with the inclusion of the genetic markers “rs1176744” (HTR3B), “rs10042486” (HTR1A), “rs936461” (DRD4), “rs179997” (ATXN1), “rs1076562” (DRD2), “rs3773678” (DRD3), “rs167771” (DRD3), “rs1587756” (DRD3), “rs134655” (KREMEN1), “rs3892097” (CYP2D6*4), “rs1341239” (PRL),”rs4975646” (SLC6A3),”rs1333302” (SLC6A2), as well as non-genetic factors such as gender, age and dose of antipsychotic in chlorpromazine equivalent (CPZeq). The developed pharmacogenetic panel can be considered as biological predictors of the development of antipsychotic-induced HP in schizophrenia before the appointment of pharmacotherapy.

Objective. Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of schizophrenia. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. Variants of ANKK1, specifically rs2734849, may function to affect DRD2 expression and density via regulating the transcription factor NF-κB. We examined whether the functional polymorphism ANKK1 rs2734849 is associated with schizophrenia. Methods. We recruited 468 patients with schizophrenia (235 women / 233 men) and 126 healthy individuals (62 women / 44 men) in Russian population of Siberian region. The polymorphism rs2734849 in the ANKK1 gene was genotyped with “Step One Plus”, using the kit “TaqMan SNPGenotyping Assay” (Applied Biosystems, USA). Statistical analysis was carried out using the SPSS software package for Windows, version 21.0. Genotype and allele frequencies were compared between groups of schizophrenia patients and healthy controls using the χ2 , Fisher tests. Results. The average age of patients with schizophrenia in the general group was 42.1 ± 12.4 years, in the group of men with schizophrenia - 37.8 ± 11.9 years, in the group of women with schizophrenia - 45.2 ± 13.9 years. The duration of the disease in the general group was 13 (6; 22), in the group of men with schizophrenia 11 (5; 18), in the group of women with schizophrenia 15 (7; 26), Me values were indicated (25% Q - 75% Q). The results on the allele frequencies of ANKK1 rs2734849 obtained for the control group in our study (rs2734849 MAF 45%) are comparable with the data for Europeoids (MAF 50%) presented in the 1000 Genomes project. The frequency of genotypes (р=0.37) and alleles (р=0.73) of the polymorphic variant ANKK1 rs2734849 in patients with schizophrenia did not differ from those in control subjects. Comparison of the ANKK1 rs2734849 genotypes and alleles distribution in the groups of men and women with schizophrenia, as well as a comparison of these groups with the corresponding by sex control persons, did not reveal statistically significant differences. Perhaps this is due to the insufficient size of the group of healthy controls. It is possible due to the complex nature of the pathophysiological processes underlying schizophrenia. Conclusion. The functional polymorphism rs2734849 in the ANKK1 gene was not associated with schizophrenia in Russian population of Siberian region.

Oxidative stress is an important component of the pathogenesis of type 2 diabetes mellitus (T2D). Glutathione peroxidase 2 is one of the antioxidant defense enzymes which uses glutathione as a co-substrate to reduce hydrogen peroxide and has the highest expression in the pancreas, an organ that is directly related to the development of diabetes. However, there is no data on the association of GPX2 with a predisposition to T2D. The aim of the study was to investigate the association of rs4602346 (A>G) in the intron of the GPX2 gene with a risk of T2D, as well as the effect of this SNP on blood plasma redox homeostasis. The study included 3197 unrelated individuals of Slavic origin, including 1570 patients with T2D and 1609 age- and sex-matching healthy volunteers. GPX2 gene polymorphism was genotyped using real-time PCR on a CFX96 Touch Bio-Rad thermal cycler. The G/G genotype was associated with an increased risk of the disease (OR 1,41, 95% CI 1,02-1,96, P=0,039, recessive model). The identified association retained its significance even after correction for gender, age, and body mass index (ORadj 1,50, 95% CI 1,04-2,16, Padj=0,03). Gender-stratified analysis revealed that the established association of rs4902346 was characteristic only for diabetic males (ORadj 2,09, 95% CIadj 1,22-3,59, Padj=0,0065), and was not observed in diabetic females (P>0,05). Assessment of redox status showed an increase in the content of hydrogen peroxide and a decrease in the level of total glutathione in the plasma of patients compared with the control (P <0.05). A correlation analysis found that patients’ hydrogen peroxide levels are directly proportional to their fasting blood glucose concentrations. An analysis of the relationships between genetic and biochemical data showed that the G/G genotype rs4902346 is associated with a decrease in the content of reduced glutathione in the plasma of female patients with T2D (P=0,0086). Thus, we identified for the first time the association of rs4902346 with an increased risk of T2D and showed significant gender differences in the associations of the GPX2 gene with the studied phenotypes.

The aim of the study was to analyze large rearrangements in the CFTR gene in patients with cystic fibrosis in the Russian Federation in 2017. The Cystic Fibrosis Patients Registry of the Russian Federation for 2017 includes data from 3096 patients from 81 regions of the Russian Federation. To date, more than 2,000 mutations or variants of the nucleotide sequence of the CFTR gene have been described. In the Cystic Fibrosis Patients Registry of the Russian Federation for 2017, 196 pathogenic CFTR variants are given. Pathogenic variants are found both in the coding and in the intron regions, and in the regulatory regions of the CFTR gene. The CFTR gene has relatively few (about 2.5%) large rearrangements, but among mutant chromosomes in which genetic variants were not identified by standard methods, such rearrangements account for up to 20%. According to the Registry of 2017, 21 patients were identified that carried large rearrangements in their genotype. The rearrangements CFTRdele12,13del16, CFTRdele19-22 (17a-19), CFTRdele8 (7*), CFTRdele2-8 (2-7*) are not described in international databases. The clinical characteristics of patients with extensive rearrangements in the genotype did not differ in basic characteristics from patients with “severe” genotypes. The presence of a genetic variant in the genotype that determines the preserved function of the pancreas leads to the preservation of gland function in patients with large rearrangements in the genotype.

Polymorphism C1173T of the VKORC1 gene is one of the key factors determining both ethnic and individual differences in the sensitivity to the anticoagulant warfarin and its maintenance dose in patients in the treatment of thrombosis-dependent diseases. In this regard, at the population level the VKORC1 C1173T polymorphism was studied in indigenous populations of the Forest Nenets (the Yamal-Nenets Autonomous Okrug) and Nganasans (the Taimyr Peninsula of the Krasnoyarsk region). Genotyping of C1173T single nucleotide substitution in the VKORC1 gene was carried out in real time using competing TaqMan probes. It was revealed that the variant VKORC1 1173T occurs with a high frequency in the studied populations: 67% in Forest Nenets and 94% in Nganasans. This indicator is significantly higher than that of Europeans, and has a similar distribution pattern with that of Asians. The results of our study expand knowledge about VKORC1 gene polymorphism in human populations, and also promote the development of personalized medicine in relation to indigenous people of Siberia, since the genetic status of a person with variant 1173T can be taken into account at an individual level in order to achieve the most safe and effective warfarin therapy of thrombosis-dependent diseases.

The prognosis of treatment for tuberculosis, as a multifactorial disease, depends on the interaction of genetic and environmental factors, therefore, the identification of genetic markers that can determine the state of immunological resistance of the body and thereby the effectiveness of its cure is promising. The results of the observation of 337 patients with various forms of pulmonary tuberculosis taking the main course of treatment are presented. Of these, 259 were determined as indicators-markers of genetic identification, allele-specific PCR variants of deletion polymorphism of the GSTM, GSTT and CYP2E1 genes.