Objective. To systematically review and critically appraise current evidence on genetic markers associated with the efficacy of anti-VEGF therapy in neovascular age-related macular degeneration (nvAMD). Methods. A literature analysis covering the period 2005–2025 was performed, including candidate gene studies, meta-analyses, and genome-wide association studies (GWAS). Genetic variants in CFH, ARMS2/HTRA1, VEGFA, KDR, IL8, and SIRT1 genes were examined. Results. The most reproducible associations with anti-VEGF response were found for CFH rs1061170 (Y402H), ARMS2 rs10490924, IL8 rs4073 (-251A/T) и VEGFA rs699947 polymorphisms. According to meta-analyses, carriage of the CFH rs1061170 risk allele is associated with reduced functional response (pooled OR=1.34, 95 % CI 1.10–1.63). However, the effect size is modest, results differ between European and Asian populations, and large RCTs have not confirmed the clinical utility of single SNPs. None of the studied markers possess sufficient predictive value for standalone use in routine practice. Conclusion. Genetic markers associated with anti-VEGF therapy efficacy in nvAMD show moderate and heterogeneous effects. The development of polygenic prognostic models combining multiple SNPs with clinical and imaging parameters is a promising direction.
Introduction. Cardiac surgery patients are at high pharmacological risk due to comorbidities, polypharmacy, and cardiopulmonary bypass. Search methods. A literature search was conducted in PubMed/MEDLINE, Web of Science, Scopus, and eLibrary.ru (2015-2025) using keywords: “pharmacogenetics AND cardiac surgery”, “warfarin pharmacogenetics”, “clopidogrel CYP2C19”, “SLCO1B1 statin myopathy”, “drug-gene interactions”. In total, 42 sources were selected and analyzed. Inclusion criteria: original studies, meta-analyses, systematic reviews, and clinical guidelines in English or Russian. Exclusion criteria: single case reports, experimental studies, conference abstracts without full text. Results. VKORC1 and CYP2C9 polymorphisms account for 50–60 % of warfarin dose variability; genotyping reduces bleeding risk and accelerates time to therapeutic INR. Loss-of-function CYP2C19 alleles impair clopidogrel activation, increasing ischemic event risk. The SLCO1B1 variant is associated with higher risk of statin-induced myopathy. In the Russian population, the frequency of clinically relevant alleles is comparable to European populations. Drug — gene and drugdrug-gene interaction concepts may potentiate adverse outcomes. Implementation of pharmacogenetic testing is limited by organizational, financial, and educational barriers. Conclusion. For cardiac surgery patients, a multiparametric algorithm incorporating multilocus genotyping (CYP2C9, VKORC1, CYP2C19, SLCO1B1, ABCG2), clinical factor assessment, and drug interaction evaluation is the most promising strategy.
Introduction. Lurasidone is an atypical antipsychotic with high affinity for 5-HT₂A, 5-HT₇, and DRD2 receptors; however, its use is limited by interindividual pharmacokinetic variability and dose-dependent adverse effects. Multi-omics approaches offer opportunities for personalized dosing. Objective. To systematically review evidence on genomic, transcriptomic, and epigenomic biomarkers associated with lurasidone efficacy and safety. Methods. A literature search was conducted in PubMed, Scopus, and RSCI (2010–2026) using keywords: lurasidone, pharmacogenomics, CYP3A4, HTR1A, microRNA, therapeutic drug monitoring. Of 187 initially identified publications, 83 sources were selected after screening. Results. The rs6295 polymorphism of the HTR1A gene is associated with lurasidone efficacy in European schizophrenia patients. CYP3A4 is the main metabolizing enzyme: CYP3A4*1G (rs2242480) significantly affects clearance (CL/F: C/C — 330 L/h, T/T — 441 L/h); CYP3A4*15 requires dose adjustment up to 240 mg/day in carriers. In hepatic impairment, dose reduction to 20–40 mg/day is recommended. Transcriptomic studies identified 1907 differentially expressed genes, including modulation of PER1 and BMAL1, as well as neurotransmitter imbalance. MicroRNAs (miR-181b, miR-21, miR-122) are promising biomarkers for response prediction and CYP activity monitoring. Lurasidone monotherapy efficacy in bipolar II depression does not exceed 41.3 %. Conclusion. The most clinically relevant markers are CYP3A4 (rs2242480, CYP3A4*15) and HTR1A (rs6295) polymorphisms, as well as microRNAs. Prospective studies are required to validate multi-omics panels in clinical practice.
Background. The therapeutic response to ACE inhibitors in hypertension is variable and depends on a combination of clinical, behavioral, and pharmacogenetic factors. Mathematical modeling allows us to assess their contribution to achieving the target values of blood pressure. Objective. To determine the factors associated with the achievement and non-achievement of target blood pressure values in patients with arterial hypertension receiving ACE inhibitors in monotherapy. Materials and methods. A single-center observational pharmacogenetic study was conducted in the period from February to May 2025. Comparison groups were formed to achieve the target blood pressure values: <140/90 mmHg and ≥140/90 mmHg. The pharmacogenetic profile of patients was assessed by the presence/absence of polymorphisms of the ACE I/D (rs1799752) and CES1 (c.1168-33C>A). The outcomes of therapy were considered to be the achievement of target values of BP, ΔSAD, and ΔDAD. The following parameters were selected as the studied confounders of the regression model: the number of polymorphic D alleles in the gene ACE; the number of polymorphic C alleles in the gene CES1, age, the amount of salt consumed per day, the number of cigarettes smoked per day. Results. The study included 90 patients of whom: 39 reached the target blood pressure values (43.3%), and 59 did not (56.7%). An increase in the number of ACE D-alleles was associated with an increase in SBP after therapy by 23.5 mmHg (95% CI: 20.68-26.41, p <0.001), DBP by 4.67 mmHg (95% CI: 3.59-5.94, p <0.001). An increase in salt intake by 1 g/day was accompanied by an increase in SBP by 0.54 mmHg (p=0.024), DBP – by 0.20 mmHg (p=0.041). Mathematical models explained 75.7% of SAD variability and 43.9% of DBP. The AUC of the logistic model was 0.97. Conclusion. The number of polymorphic D alleles is associated with a therapeutic response and can be considered as a preliminary marker of ACE inhibitor efficacy (p<0.001).
Background. In the context of predictive medicine, personalized assessment of ischemic stroke risk based on molecular genetic testing is becoming increasingly relevant. Polymorphisms in folate cycle genes (MTHFR, MTR, MTRR), leading to hyperhomocysteinemia, cause endothelial dysfunction and accelerate atherogenesis. The role of the renin-angiotensin system (RAS) is no less important: genetic variations in the AGT and NOS3 genes are associated with arterial hypertension and altered vascular tone, which creates a predisposition to cerebrovascular accidents. Objective. To identify associations between polymorphisms of folate cycle and renin-angiotensin system genes and the development of acute ischemic stroke and transient ischemic attack (TIA). Methods. The observational study included 492 patients who were treated in hospital at the Institution Clinical Hospital No. 1 of the Presidential Administration of the Russian Federation in the period 2022–2025 and who signed informed consent for molecular genetic testing. A comparative analysis of clinical, laboratory, instrumental, and molecular genetic data (polymorphisms of MTHFR, MTR, MTRR, AGT, NOS3, and AGTR1) was performed between the ischemic stroke group (n=426) and the TIA group (n=66). Statistical analysis was carried out using the Mann-Whitney U test and Pearson's chisquared test. Results. Stroke patients were older (73 vs 66 years, p=0.005) and more frequently male (43.4 % vs 27.3 %, p=0.013). The stroke group had significantly higher triglyceride levels (p < 0.001) and potassium levels (p < 0.001), as well as a higher frequency of pathological MRT findings (p < 0.001). Genetic analysis revealed a significant predominance in the stroke group of homozygous CC genotypes for MTHFR C677T (p=0.001), AGT174 (p=0.004), AGT235 (p < 0.001), and NOS3 (p=0.028). In contrast, the TIA group more frequently carried TT genotypes for C677T AGT235, and NOS3, as well as the heterozygous CT genotype for AGT174. Conclusion. Molecular genetic testing of polymorphisms in folate cycle and renin — angiotensin system genes represents a promising tool for risk stratification and differential diagnosis of ischemic stroke versus TIA, and may serve as a foundation for personalized pharmacotherapy in the nearest future.
The article presents the key decisions and priority directions for the development of the specialty "Clinical Pharmacology" adopted following the congress of Clinical Pharmacologists "ClinPharm-Expert 2026," held on May 21–22, 2026 in Moscow within the framework of the IV Russian Congress "Pharmacotherapy Safety 360°: Noli nocere!" The document summarizes the main provisions of the congress Resolution, which specifies the pathways for implementing the Healthcare Development Strategy of the Russian Federation until 2030. Special attention is given to strengthening the role of clinical pharmacologists as key ambassadors of personalized medicine technologies, including pharmacogenetic testing and therapeutic drug monitoring. The Resolution formulates 19 organizational and educational measures aimed at updating the regulatory framework, integrating clinical pharmacologist consultations into the clinical-statistical groups system, developing networking educational programs, establishing a National Research Center for Clinical Pharmacology, and enhancing the prestige of the specialty ahead of its 30th anniversary in 2027. The article also highlights the inclusion of the journal "Pharmacogenetics and Pharmacogenomics" in the Scopus database and the "White List" of scientific periodicals. The article is intended for clinical pharmacologists, healthcare administrators, physicians of related specialties, and professionals in personalized medicine.
Background. High variability in individual response to controlled ovarian stimulation remains one of the main challenges in assisted reproductive technologies, and the prognostic value of most studied genetic markers shows conflicting results. Objective. To evaluate the association of gonadotropin and sex steroid receptor gene polymorphisms with clinical pregnancy rates in women with tuboperitoneal infertility undergoing in vitro fertilization programs. Materials and methods. This prospective pilot study included 96 patients (25–35 years old) with tuboperitoneal infertility and normal ovarian reserve. Two groups were formed: Group 1 (n=48) — pregnancy on the first attempt; Group 2 (n=48) — patients with a history of three or more previous unsuccessful attempts. The patients received standardized therapy using a short protocol with gonadotropin-releasing hormone antagonists and recombinant FSH. Genotyping was performed using microarray analysis (Infinium Global Screening Array-24 v3.0, Illumina). Results. For the rs3020394 polymorphism of the ESR1 gene, a protective association was established between the A/A genotype (p=0.025; OR=2.553; 95% CI 1.120-5.820) and a negative predictive value of the homozygous G/G genotype. An association was found between the heterozygous C/T genotype of the rs2234693 (PvuII) polymorphism in the ESR1 gene and an unfavorable IVF outcome (p=0.024; OR=0.593; 95% CI 0.170-0.890). Conclusion. The identified associations demonstrate the need for the development and further implementation of pharmacogenetic testing in the comprehensive evaluation of patients with tuboperitoneal infertility as a tool for personalized medicine.
Relevance. The safety of stroke pharmacotherapy against the background of polypharmacy is of paramount importance in modern clinical practice. Genetic polymorphisms of cytochrome P450 genes, including the CYP2C9 gene, significantly contribute to drug responses and drug-drug interactions. The alleles with reduced function are CYP2C9*2 (R144C, rs1799853) and CYP2C9*3 (I359L, rs1057910). Objective. Analysis of the frequency distribution of alleles and genotypes of the CYP2C9 gene (rs1057910, rs1799853) in stroke patients, taking into account possible drug interactions in real clinical practice in Arkhangelsk. Materials and methods. A cross-sectional study was conducted on a sample of patients diagnosed with stroke, hospitalized in the neurology department of the regional vascular center of the First City Clinical Hospital named after E. E. Volosevich of the Arkhangelsk Region. Patients were divided into two groups: those initially hospitalized and those readmitted. Polymorphic variants of the CYP2C9 gene were studied: rs1057910 (Ile359Leu), rs1799853 (Arg144Cys) by real-time polymerase chain reaction using a Bio-Rad CFX96 Touch amplifier. Results. The study included 81 patients aged 43 to 95 years with a diagnosed stroke. Statistically significant differences were observed in the blood potassium level of 4.2 (3,865–4,615) in the group with primary hospitalization and 4,575 (4.31–4,845) in the group with repeated hospitalization (р=0,022). Carriers of low-functional variants of the CYP2C9 gene were identified in both groups: Ile359Leu (rs1057910), Arg144Cys (rs1799853). Statistically significant differences between the CYP2C9 gene allele variants and the frequency of repeated hospitalizations are not detected (p>0.05). The analysis of pharmacotherapy in the study sample of post-stroke patients revealed potential undesirable drug interactions between clopidogrel and acetylsalicylic acid as a risk factor for side effects. Conclusion. The study conducted in real clinical practice demonstrates the importance of introducing pharmacogenetic testing in stroke patients from the perspective of identifying potential drug interactions.
Background . The effectiveness of in vitro fertilization (IVF) programs remains limited, which necessitates the search for new prognostic markers. The CYP2A6 gene is expressed in estrogen-sensitive tissues, and its activity is regulated by sex steroids, but the contribution of its polymorphisms to IVF outcomes remains poorly understood. Objective. To determine the association between polymorphic variants of the CYP2A6 gene and IVF outcomes in patients with tubal-peritoneal infertility. Materials and methods . A prospective pilot study included 96 women (mean age 31.4 ± 3.7 years) with tuboperitoneal infertility. All participants received therapy according to a short protocol with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone. Nine polymorphisms of the CYP2A6 gene were analyzed by genome-wide genotyping on the Illumina iScan platform. Statistical processing was performed using Student's test, χ ² test and Monte- Carlo permutation method. Results . The rs8192733 C/C genotype is associated with a favorable outcome (OR = 6.922; 95 % CI: 2.592–18.486; p <0.001), while the G/G genotype is associated with a risk of implantation failure (OR = 0.053; 95 % CI: 0.017–0.160; p <0.001). For rs57837628, the G/G genotype is associated with a 2.4-fold increase in the odds of pregnancy (OR = 2.369; 95 % CI: 0.946–5.936; p = 0.010), the A/G genotype is associated with an unfavorable outcome (OR = 0.231; 95 % CI: 0.096–0.559; p <0.001). Significance was confirmed by the permutation test (p-perm <0.05). Conclusion . An association was established between the CYP2A6 polymorphisms rs8192733 and rs57837628 and the outcomes of IVF programs in tubal-peritoneal infertility. The obtained data demonstrate the potential for their use as additional criteria in personalized patient management protocols in ART cycles.
Background. The prevalence of clopidogrel resistance among patients with cardiovascular diseases (CVD) reaches 30–40 %, significantly increasing the risk of recurrent myocardial infarction (MI) and other thrombotic events. Genetic polymorphisms in CYP2C19 and ABCB1 account for up to 40 % of the variability in antiplatelet response; however, data on Turkic populations, including the Chuvash, remain fragmentary. Objective. To determine the frequencies of CYP2C19 (*2, *3, *17) and ABCB1 C3435T polymorphisms, as well as their association with recurrent MI and clopidogrel resistance in patients of Chuvash ethnic origin with CVD, including acute coronary syndrome (ACS). Materials and methods. This prospective cohort study included 216 Chuvash patients (mean age 66.5 years) with CVD, including ACS, receiving dual antiplatelet therapy with clopidogrel. Genotyping of CYP2C19 (*2, *3, *17) and ABCB1 (3435C>T) polymorphisms was performed using real-time PCR. In a subgroup of ACS patients (n=30), ADP-induced platelet aGGreGAtion was assessed turbidimetrically on day 7 of therapy. Results. Among Chuvash patients, a high frequency of minor alleles was observed: ABCB1 C3435T — 60.6 %, CYP2C1917 (–806C>T) — 28.7 %, whereas the frequencies of CYP2C192 and CYP2C193 were low (9.05 % and 1.85 %, respectively). Heterozygous CT genotype of CYP2C19*17 was associated with a higher rate of recurrent MI both in the overall cohort (19.8 % vs. 8.5 % in CC carriers; p=0.049) and in the ACS subgroup (30.2 % vs. 12.9 %; p=0.037, p~CC–CT~ =0.044). Laboratory platelet aGGreGAtion assessment revealed that the highest proportion of antiplateletresistant patients was observed among heterozygotes carrying the *1/*17 genotype (rapid metabolizer phenotype), whereas no resistance cases were recorded among *17/*17 homozygotes (ultrarapid metabolizers). No statistically significant associations with recurrent MI were found for CYP2C192, CYP2C193, or ABCB1 polymorphisms. Conclusion. In Chuvash patients with CVD, including ACS, heterozygous carriage of CYP2C1917 is associated with recurrent MI, which contradicts the expected enhancement of clopidogrel antiplatelet effect (rapid metabolizer phenotype). This may indicate possible phenoconversion due to the interplay of genetic factors (ABCB1 C3435T) and drug — drug interactions (concomitant omeprazole use).
Background. Prescription of dangerous and undesirable drug combinations occurs in healthcare systems of most countries worldwide. Among drugs with the highest risk in such combinations, statins are considered particularly hazardous due to their significant metabolic activity. In the healthcare system of Kazakhstan, this problem remains poorly studied, and the structure of genetic predisposition to adverse effects is unknown. Objective. To determine the frequency of SLCO1B1 gene polymorphism in patients with coronary artery disease of the Kazakh population of East Kazakhstan and its association with the efficacy and safety of atorvastatin therapy. Methods. A cross-sectional clinical-genetic study was conducted. The study did not involve any active intervention in the ongoing treatment of patients prescribed by physicians. Medical records containing prescription data from inpatient and outpatient settings were analysed. The presence of SLCO1B1 (c. 521T>C) polymorphisms of the OATP1B1 transporter protein was assessed. Results. The study included 178 individuals (108 men and 70 women) aged 40 to 70 years (mean age 61.1±7.8 years). All patients were of Kazakh ethnicity. In the examined group of patients receiving statin therapy, a significant frequency of genetic variants associated with an increased risk of statin-related complications was identified. Significant differences in the frequency of clinical manifestations of drug-induced muscle adverse effects were observed for the SLCO1B1 gene in carriers of the homozygous CC genotype (χ² = 23.31, p < 0.001). A marked increase in creatine phosphokinase activity (3.39-fold, p < 0.001) and a reduction in atorvastatin efficacy were also observed. Conclusions. In the studied Kazakh population, analysis of the SLCO1B1 (c. 521T>C) polymorphism can be recommended as a genetic marker of the risk of adverse reactions during lipid-lowering therapy with statins (atorvastatin), as this polymorphism reduces treatment efficacy and increases the risk of side effects.
Objective . The study aimed to assess pharmacogenetic characteristics of prescribed versus taken pharmacotherapy in patients with cardiovascular diseases (CVD). Materials and methods. A total of 813 electronic health records (EHRs) were selected from available electronic medical documents (n=8791) of CVD patients, using probability cluster sampling method. Unstructured text from the EHRs (n=813) was used to create a database characterizing gender, age, ICD-10 codes, prescribed and taken pharmacotherapy, international nonproprietary names (INNs), and pharmacogenes corresponding to each case of pharmacotherapy. Pharmacogenetic drugs and associated pharmacogenes were identified using database ClinPGx.org. Results . Patients aged 62 years (IQR 56–68 years); 70.2 % men. The list of prescribed drugs comprised 347 INNs; the list of taken drugs comprised 253 INNs; both lists comprised 435 INNs, suggesting a mismatch between the lists. Numbers of INNs per document ranged from 1 to 23 for taken drugs (Me=6, IQR 3–9; n=385) and from 1 to 20 for prescribed drugs (Me=6, IQR 4–9; n=724), p > 0.05. The study identified 1120 pharmacogenes. Number of associated pharmacogenes per INN did not significantly differ between the lists of prescribed and taken drugs (1, IQR 0–7). However, the differences were found between the incidence rates of individual pharmacogenes. Pharmacogenes UGT1A9, UGT1A3, AGTR1, KIF6, and SCAP were significantly more often associated with prescribed drugs (p <0.05); ABCB1, NOS3, GNB3, ADRB1, and ADD1 were significantly more often associated with taken drugs (p <0.05). Conclusion . The study demonstrated a mismatch between the pharmacogenetic profiles of prescribed versus taken pharmacotherapy in CVD. Drug-gene interactions may affect treatment adherence.
Relevance. Despite the use of antipsychotic drugs is still one of the most effective treatment methods of schizophrenia, the 20–30 % of patients do not respond adequately to pharmacotherapy. This inefficacy may stem from genetic variability, which influences drug metabolism, adverse reactions, and treatment response, alongside gene-environment interactions. This study aimed to investigate the association between polymorphic gene loci and pharmacoresistant schizophrenia among Belarusian patients. Objective. To study the relationship of a number of polymorphic gene loci with pharmacoresistance (FR) in patients with schizophrenia, residents of Belarus. Methods. The study included 161 people with schizophrenia. The main group included 104 patients with no improvement when treating with two or more antipsychotics (including an atypical antipsychotic) for 6 to 8 weeks; the comparison group included 57 patients with positive response to pharmacological treatment of schizophrenia. Pharmacogenetic testing was performed using standard methods of nucleic acid isolation and PCR analysis. 19 polymorphic loci in 15 genes (CYP2D6, CYP2C9, CYP2C19, CYP1A2; MDR1, ANKK1, HTR1A, HTR2A, SLC6A4, HTR2C, COMT, MAOA, BDNF, DRD2, UGT1A1) were genotyped. Statistical processing of clinical and genotyping data was carried out using the SPSS Statistics 20.0 program. The odds ratio (OR) and 95 % confidence interval (CI) were used as an indicator of the relationship between alleles and genotypes with the risk of developing PR. Results. Comparison of the genotypes and alleles frequencies in the studied groups of patients with schizophrenia revealed an association of PR in carriers of alleles — A (CYP2D6, rs3892097) (χ 2 =4.124; p=0.042), G (COMT, rs4680) (χ 2 =9.006; p=0.003); AG genotype (CYP2D6, rs3892097) (χ 2 =6,647; р=0,01), CC genotype (HTR1A, rs6295) (χ 2 =5.522; p=0.019). Further analysis revealed an increase in the risk of PR when these alleles were combined with other gene loci. Patients with pharmacogenetic profiles A-/A(CYP2D6 / CYP1A2), (OR 2.926; CI 1.206–7.102); A-/B-/T(CYP2D6 / CYP1A2 / MDR1), (OR 4.833) had an increased risk of developing FR; CI 1,753–13,328); G-/L(COMT / SLC6A4), (OR 3,172; CI 1,500–6,709); G-/LL (COMT / SLC6A4), (OR 6,923; CI 1,900–25,227); G-/LL/T(COMT / SLC6A4 / MDR1), (OR =11.143; CI 2.415–51.414); CC/T(HTR1A / MDR1), (OR 2.564; CI 1.120–5.873). Conclusion. A study using pharmacogenetic testing of residents of Belarus with schizophrenia revealed a significant association of the risk of PR with polymorphic loci of the genes CYP2D6 (rs3892097), HTR1A (rs6295), COMT (rs4680). An increased risk of PR was observed when the identified alleles were combined with polymorphic loci of the CYP1A2 (rs762551), MDR1 (rs1045642), and SLC6A4 (5-HTTLPR) genes. Pharmacogenetic risk profiles for the development of PR during antipsychotic therapy in patients with schizophrenia are described.
Background. According to Russian and European clinical guidelines, methotrexate (MTX) is used for initial therapy of rheumatoid arthritis (RA), under regular medical and laboratory monitoring to prevent adverse reactions (AE). The incidence of AEs in MT reaches 72.9 %, with gastrointestinal reactions (20–30 %), hepatotoxicity (10–15 %), and hematological disorders (5–10 %) predominating. Hepatotoxicity requires long-term monitoring of liver function according to DILIN recommendations, while pulmonary complications (1–2 %) require immediate discontinuation of therapy. Polymorphisms of MT metabolism genes (ABCB1, SLC19A1, FPGS, GGH, ATIC, MTHFR, DHFR), by altering its pharmacokinetics and pharmacodynamics, determine individual tolerability of the drug. Pharmacogenetic testing enables the development of personalized approaches to RA therapy, reducing the risk of MT discontinuation and switching to expensive biologics. Objective. To develop a pharmacogenetic model for predicting the risk of developing PD MT in patients with RA based on gene polymorphisms of key proteins involved in methotrexate metabolism. Methods. The study included 294 patients with a confirmed diagnosis of RA who received MT monotherapy for 6 months. The associations between single-nucleotide polymorphisms (SNPs) of nine genes involved in MT metabolism and transport (ABCB1, ADA, AMPD1, ATIC, FPGS, GGH, ITPA, MTHFR, SLC19A1) and the development of PD were studied. Genotyping was performed by polymerase chain reaction (PCR) using domestically produced kits. A comprehensive statistical analysis was performed using multivariate dimensionality reduction (MDR) with 10-fold cross-validation, sensitivity and specificity assessment, and entropy analysis to identify epistatic gene interactions. Results. PDs were recorded in 82 patients (27.9 %), primarily hepatotoxicity (17 %). Primary automated models involving 1–3 genes demonstrated low reliability, while data-driven models considering the biological role of genes demonstrated high predictive value. Five-gene and six-gene models, including polymorphisms of the transport systems (SLC19A1, ABCB1), polyglutamation (GGH, FPGS), and adenosine pathway (ATIC), proved optimal, with a maximum sensitivity of 91.5 % and specificity of 69.3 %. Conclusion. A combined analysis of gene polymorphisms involved in MT transport and metabolism significantly improves the accuracy of predicting MT tolerance in patients with RA. A six-gene model combining the SLC19A1, ABCB1, GGH, FPGS, and ATIC genes demonstrated the greatest diagnostic value. The developed "if — then" predictive rule enables a personalized approach to therapy and can be used in clinical practice to predict the risk of MT-related PD.
Relevance . The study of the prevalence of ABCB1 polymorphic markers and the prediction of clinical, laboratory and demographic parameters in patients with ischemic stroke is a relevant area of pharmacogenetics and practical neurology.Objective. To determine the frequency of ABCB1 polymorphism (C3435T, rs1045642) in patients with ischemic stroke and evaluate its association with clinical, laboratory and demographic parameters of patients. Material and methods . The study group included 120 patients with non-cardioembolic ischemic stroke. Genotyping of ABCB1 polymorphisms (C3435T, rs1045642) was performed by polymerase chain reaction. An analysis of clinical and demographic factors and distribution frequencies of ABCB1 genotypes (C3435T) was performed. Results . The CC genotype was verified in 18.0 %, CT in 56.0 %, and TT in 26.0 % of patients. The distribution of ABCB1 genotypes (C3435T, rs1045642) among patients with ischemic stroke complied with the Hardy-Weinberg law (χ²=1.81; p=0.18). When assessing the comparability of clinical and demographic characteristics and the results of genotyping for ABCB1 (C3435T, rs1045642), a statistically significant difference in the frequency of detection of diabetes mellitus and overweight in patients with ischemic stroke was noted. Diabetes mellitus and obesity were detected with a higher frequency in the group of patients carrying the CT+TT genotypes: in the presence of diabetes mellitus — 31.6 % versus 18.2 % (p=0.023); in the presence of excess body weight — 36.7 % versus 18.2 % (p=0.003). No statistically significant association with the clinical features of the course of ischemic stroke was found. Also, no characteristic differences were found between patients carrying the CT/TT genotypes (those who responded and those who did not respond to antiplatelet therapy with clopidogrel). When assessing the comparability of average quantitative laboratory parameters in carriers of the CC and CT+TT genotypes of the ABCB1 polymorphism (C3435T, rs1045642), it was revealed that in the general blood test, the average level of leukocytes and neutrophils was statistically significantly higher in the group of patients with the CC genotype. Conclusion . The obtained data may influence the choice of priority for the implementation of pharmacogenetic tests both in cerebrovascular pathology and in other diseases.
This article investigates the factors hindering the widespread implementation of pharmacogenetic tests into routine clinical practice. Based on an analysis of international and Russian physician surveys (ESC, 2026; Russian surveys 2022–2025), the main barriers to the broad adoption of pharmacogenetic testing are examined. It is shown that despite a high level of physician readiness to use pharmacogenetic tests (up to 73 % of respondents), only one-third of specialists have actual access to them. Three key groups of problems are identified: a lack of knowledge and skills for result interpretation; insufficient infrastructure (high cost, long turnaround times, lack of standardization); and the absence of mandatory provisions in clinical guidelines. Overcoming these barriers requires a comprehensive approach, including improving the regulatory framework, training healthcare professionals, enhancing infrastructure, and providing economic justification.
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.
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. 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.
