Relevance. Pharmacogenetics is one of the leading areas of personalized medicine, allowing the prediction of the effectiveness and safety of medicines

in a particular patient. This study analyzed the presence of CYP3A4 gene allele mutations and their relationship with the effectiveness of therapy.

Objective. This study aimed to evaluate the effect of the genetic polymorphism A/G (rs2740574) of the CYP3A4 gene, as well as polymorphisms CYP3A4_2 Leu293Pro (rs28371759) and CYP3A4 Phe189Ser (rs4987161) in patients with coronary heart disease on the lipid-lowering efficacy of atorvastatin in real-world practice.

Materials and methods. This study included 96 patients with coronary artery disease who received atorvastatin therapy. Molecular genetic analysis of CYP3A4 gene polymorphisms was performed using real-time polymerase chain reaction. Statistical data processing was performed using STATA 14 software.

Results. The frequency of the G allele (rs2740574) in the studied sample was 8.3 %, which differed significantly from that of the all-Russian (4 %, p = 0.0095) and European (3.63 %, p = 0.0005) populations. The frequency of the minor C allele for the CYP3A4_2 Leu293Pro (rs28371759) polymorphism was 0.5%, which was significantly different from the global and European frequencies (p < 0.001). Polymorphism CYP3A4 Phe189Ser (rs4987161) was not detected in the sample. Carriers of the G allele (rs2740574) (n = 15) showed a significant decrease in total cholesterol (from 5.38 ± 1.49 to 3.23 ± 0.96 mmol/l, p = 0.0019) and LDL-C (from 3.54 ± 1.17 to 1.58 ± 0.62 mmol/l, p = 0.0004) during atorvastatin therapy. The effect of other polymorphisms on the lipid profile could not be assessed due to their low prevalence.

Conclusion. Unique frequencies of CYP3A4 gene alleles, which differ from the reference populations, have been identified in patients with coronary heart disease in Arkhangelsk. The presence of the G allele (rs2740574) is associated with a more pronounced lipid-lowering response to atorvastatin therapy. The findings highlight the importance of pharmacogenetic studies for the personalization of statin therapy.

Relevance. The steady increase in the incidence of breast cancer (BC), as well as associated mortality and disability of the population, determines the relevance of the search for effective treatment and prevention of this pathology.

Objective. Evaluation of differences in the effectiveness of chemotherapy for BC depending on the age, stage, and biological subtype of the tumor, considering the deletion status of the GSTT1 and GSTM1 genotypes in patients.

Materials and methods. Data from 132 patients with BC who received chemotherapy treatment from 2013 to 2021 were analyzed. Polymorphic GSTM1 and GSTT1 variants were genotyped using multiplex polymerase chain reaction, followed by analysis of the melting curves of the reaction products.

Results. The presence of the "null" genotype of GSTM1 and GSTT1 reduced the risk of relapse in patients with stage III disease by 0.52 times (95 % CI 0.29–0.89, p = 0.023) and 0.4 times, respectively (95 % CI 0.098–0.99, p = 0.049). Patients with luminal B HER2-positive breast cancer and GSTM1-0 had no fatalities. The risk of relapse was reduced in women with luminal B HER2-negative breast cancer subtype in the GSTM1-0 genotype group. In patients with luminal A, the overall survival (OS) with the GSTT1 wild type was 75.5 (±12.3) %, with GSTM1-0 there were no lethal outcomes (OR = 0.034, 95 % CI 0.02–0.045, p = 0.001), with luminal B HER2-negative subtypes, OS with the GSTT1 wild type was 69.9 (±8.5) % versus no lethal cases with the null genotype (OR = 0.035, 95 % CI 0.025–0.044, p = 0.001)).

Conclusion. The results of our study showed a significant effect of the GSTT1 and GSTM1 gene deletion polymorphism on relapse-free survival in patients with stage III disease and hormone-dependent breast cancer.

Background. Morphine pharmacokinetics in cancer patients are characterized by high interindividual variability, partly due to genetic factors. The role of ABCB1 gene polymorphisms in modifying morphine exposure in this patient population has been poorly studied.

Objective. To evaluate the effect of ABCB1 gene polymorphisms rs1128503, rs2032582, and rs1045642 on steady-state plasma morphine concentrations in patients with cancer receiving palliative care.

Methods. This study included 86 patients with cancer treated in the Palliative Care Department of the Moscow Multidisciplinary Palliative Care Center of the Moscow Department of Health. All participants received stable oral morphine doses ranging from 30 to 100 mg/day. ABCB1 polymorphisms were genotyped using real-time polymerase chain reaction (PCR). Plasma morphine concentrations were determined using HPLC-MS/MS. Statistical analysis included an assessment of normality (Shapiro-Wilk test), nonparametric Mann–Whitney and Kruskal-Wallis tests, and χ², with p ≤ 0.05 considered statistically significant.

Results. In carriers of the TT genotype rs1045642, at a dose of 80–100 mg/day, the median morphine concentration was 151.8 nmol/L, exceeding the values in CT (110.4 nmol/L) and CC (83.7 nmol/L), with p = 0.097 (χ²), p ≤ 0.05 for pairwise comparisons. Similar trends were found for rs2032582 and rs1128503,

with significant differences between carriers of minor alleles. No adverse events related to the study intervention were reported.

Conclusion. Carriage of certain ABCB1 allelic variants is associated with increased exposure to morphine. Genetic predictors may facilitate individualized dosing in patients with cancer undergoing palliative care.

Background. The effectiveness and safety of dabigatran for venous thromboembolism (VTE) prophylaxis show significant interindividual variability, partially attributed to pharmacogenetic factors.

Objective. To evaluate the influence of ABCB1 (rs1045642, rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran pharmacokinetics and clinical outcomes in patients after orthopedic surgery.

Methods. The study included 60 patients who received dabigatran etexilate (220 mg/day) after total knee arthroplasty. Genotyping was performed by real-time PCR, and dabigatran plasma concentrations were measured by HPLC-MS/MS. Clinical outcomes (VTE, bleeding) were monitored.

Results. The ABCB1 3435TT genotype was associated with higher dabigatran concentrations and an increased bleeding risk, while the CES1 rs2244613 CC genotype correlated with lower concentrations and a higher thrombotic risk. A combination of ABCB1 (CC and TT) and CES1 (AA) genotypes demonstrated optimal efficacy and safety. Heterozygous carriage of all three polymorphisms had an unpredictable effect. A case of severe bleeding due to drug-drug interaction was described.

Conclusion. Genetic polymorphisms of ABCB1 and CES1 significantly influence dabigatran exposure and the risk of complications. Preemptive genotyping could personalize anticoagulant therapy to improve its safety and efficacy in post-operative patients.

Background. Treatment of drug-resistant tuberculosis is associated with numerous medical and societal problems; therefore, the search continues for

measures to improve treatment outcomes through the development of new drugs and chemotherapy regimens. Bedaquiline metabolized by the cytochrome P450 isoenzyme CYP3A4. CYP3A4 and CYP3A5 polymorphisms can lead to variability in bedaquiline plasma concentrations, which in turn affects treatment efficacy and safety. Currently, there are no data on the prevalence of CYP3A4*22 and CYP3A5*3 gene polymorphic variants among Yakuts and Russians with tuberculosis.

Objective. To study the carrier frequency of CYP3A4*22 (rs35599367) C>T and CYP3A5*3 (rs776746) A>G gene polymorphisms among Yakuts and Russians with drug-resistant tuberculosis compared to the normal variability of the studied gene allelic variants in East Asian and European populations.

Methods. A cross-sectional comprehensive study was conducted on 255 patients of Yakut and Russian ethnicity with drug-resistant pulmonary tuberculosis. CYP3A4*22 (rs35599367) C>T and CYP3A5*3 (rs776746) A>G polymorphisms were determined by real-time polymerase chain reaction. For comparative analysis, data on the carrier frequency of CYP3A4*22 and CYP3A5*3 allelic variants in East Asian and European populations were used.

Results. In patients with drug-resistant pulmonary tuberculosis, the frequency of the T allele of the CYP3A4*22 gene was significantly lower in the Siberian group compared to the frequency in the Eurasian group (p = 0.003). The wild-type genotype (CC) CYP3A4*22 was significantly more common in the Siberian group of patients than in the Eurasian group, whereas the heterozygous genotype (CT) was less represented in the Siberian population (p = 0.003). The AA genotype of CYP3A5*3 was less common in the Siberian group relative to its frequency in the Eurasian group (p = 0.021), the heterozygous AG genotype was much less frequently detected in the Siberian population of patients (p < 0.001), and the GG genotype predominated in the Siberian group and was less frequently determined in the Eurasian population (p < 0.001). The frequencies of alleles and genotypes of the CYP3A5*3 gene in patients with drug-resistant pulmonary tuberculosis did not differ between the Yakut and Russian populations. The distribution of CYP3A5*3 alleles and genotypes in the Russian population was the same as in the general European profile (p > 0.05). Differences were found between Yakuts and East Asians for all analyzed parameters (p < 0.05).

Conclusion. Features of the distribution of CYP3A4*22 and CYP3A5*3 gene allelic variants affect the rate of drug metabolism among patients of Yakut

and Russian ethnicity. Differences in allelic variants and genotypes of CYP3A4 and CYP3A5 in Russian and Yakut populations with drug-resistant pulmonary tuberculosis can significantly modify clinical efficacy and the development of adverse reactions during bedaquiline treatment, as the CYP3A isoenzyme of cytochrome P450 plays a primary role in its oxidation.