Background/Objectives: Direct oral anticoagulants (DOACs) are first-line medications for stroke prevention in non-valvular atrial fibrillation (AF). However, variability in drug response poses risks of hemorrhagic or thromboembolic events. The role of genetics in determining DOAC safety is gaining attention, but evidence linking specific genetic polymorphisms to bleeding risk is lacking. Therefore, the aim of our study was to conduct an Exome-Wide Association Study with 198 non-valvular AF patients treated with rivaroxaban or apixaban, including 97 with bleeding complications and 99 without. Methods: DOAC plasma concentrations, 6-β-hydroxycortisol and cortisol levels in urine were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single nucleotide variants (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Results: No SNVs reached Bonferroni-corrected significance in any genetic model. Polygenic risk scores (PRS) showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln Css min/D + 1 index increased with PRS, age, and 6-β-hydroxycortisol/cortisol ratio, but decreased with higher 6-β-hydroxycortisol and coronary heart disease presence. Conclusions: The findings revealed that the residual equilibrium concentration of anticoagulants, including dose-adjusted, cannot alone predict bleeding risk in non-valvular AF patients. No new genetic variants associated with bleeding risk were identified.
Background . There is a mounting evidence in the scientific literature that susceptibility to SARS-CoV-2 infection could vary. The severity of COVID-19 symptoms can range from asymptomatic to severe respiratory failure, requiring prolonged artificial ventilation. The underlying causes of this range of clinical manifestations remain unclear. Identification of the risk factors that may cause this variation in clinical symptoms is important for identifying the most susceptible populations at highest risk. This should help improve prevention measures, reduce hospitalizations, and decrease the mortality rate of the disease. Previously, an association has been found between the severity of COVID-19 and the genetic markers rs11385942 G>GA and rs657152 A>C. The aim . To assess the impact of carrying polymorphic markers rs11385942 G>GA and rs657152 A>C on the severity of COVID-19 in patients undergoing specific therapy. Materials and methods. A total of 240 patients hospitalized with a coronavirus infection were included in the study. All patients received therapy with favipiravir or remdesivir. The presence of the rs11385942 G>GA and rs657152 A>C variants was determined in all patients. The study compared the length of hospital stays, frequency of patient transfers to the intensive care unit (ICU), and frequency of clinical outcomes (recovery or death) among carriers of allelic variants of the markers under investigation. Results . There were no significant associations between the carriage of variants rs11385942 G>GA and rs657152 A>C and the duration of patients’ hospitalization, frequency of patient transfers to the ICU, and patient outcomes. Conclusion . The carriage of rs11385942 G>GA and rs657152 A>C variants did not affect the severity or type of clinical outcomes in patients with COVID-19.
Introduction . CYP2D6 is involved in the metabolism of tamsulosin, which is used to treat lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). However, the impact of carrying polymorphic variants of the CYP2D6 gene on the clinical efficacy and safety of tamsulosin therapy is still not well understood. Aim. To evaluate the impact of CYP2D6 polymorphic variants on steady state concentration of tamsulosin (Css min ), as well as their correlation with the efficacy and safety of therapy in patients with BPH. Materials and methods . A single-center prospective study included 75 patients who completed all stages of the study. The median age of the patients was 69 years, body mass index was 27.17 ± 4.86 kg/m². 56 patients (74.67%) had comorbidities, which means the presence of at least one chronic disease in addition to the diagnosis of benign prostatic hyperplasia. 26 people (34.67%) were classified as polymorbid patients, i.e. having several comorbidities at once, while 19 patients (25.33%) had no comorbidities except for benign prostatic hyperplasia. Genotyping was performed by real-time polymerase chain reaction. Css min of tamsulosin was determined by HPLC-MS/MS. Efficacy of therapy was assessed using IPSS score and Qmax. Safety was assessed based on the incidence of adverse reactions. Results. Carriage of CYP2D6*4 and CYP2D6*10 was found to be associated with statistically significant increases in Cssmin levels. However, the identified pharmacokinetic differences, carriage of CYP2D6 markers was not reflected in the clinical efficacy and safety of tamsulosin. Conclusion. CYP2D6*4 and CYP2D6*10 may affect the Css min levels of the tamsulosin, but does not affect the clinical results of treatment.
The clinical outcomes of tamsulosin therapy for LUTS/BPH patients vary, with up to one-third of patients reporting unsatisfactory results. Enhancing the effectiveness and safety of tamsulosin therapy for LUTS/BPH patients remains a significant challenge in current medical practice. Limited data exists regarding the impact of CYP2D6 genetic polymorphisms on the efficacy and safety of tamsulosin therapy. Given that tamsulosin is metabolized by CYP2D6, variations in this enzyme may influence the drug's pharmacodynamic response. The objective of this study was to evaluate the impact of CYP2D6 pharmacogenetic markers on tamsulosin efficacy and safety in patients with LUTS associated with BPH. The study included 142 male patients with LUTS and a confirmed diagnosis of BPH (N40 ICD-10). Patients were followed for a minimum of 8 weeks and underwent four examinations (at days 0, 14, 28, and 56). Treatment efficacy was assessed using the IPSS with quality of life assessment, transrectal ultrasound of the prostate with estimation of prostate volume and residual urine volume, and maximum urinary flow rate (Qmax). Allelic variants of CYP2D6 (*2, *3, *4, *6, *9, *10, and *41) were determined by polymerase chain reaction in all patients.. In the subgroup with moderate symptoms, individuals classified as poor and intermediate metabolizers exhibited significantly higher ΔQmax compared to normal metabolizers (4.25 [2.5; 6.1] vs. [0.6; 4.3], p=0.001826). Moreover, carriers of the CYP2D6*10 CT heterozygous genotype demonstrated lower IPSS scores at the last two visits compared to those with the CC genotype (visit 3: -7.45 ± 3.93 vs. -5.25 ± p=0.05; visit 4: -8.91 ± 3.88 vs. -6.31 ± 5.7), as well as reduced IPSS irritative symptoms at visit 2 (-3.87 ± 2.70 vs -2.47 ± 3.1, p=0.05), and a significant increase in ΔQmax ([2.5; 5.9] vs. [0.6; 4.7], p=0.01). In the subgroup with severe symptoms, individuals with CYP2D6*41 GA + AA genotypes exhibited less residual urine volume following therapy compared to those with the GG genotype ([15.0; 32.0] vs. [3.0; 19.0], p=0.007029). The CYP2D6 polymorphic variants did not impact the tamsulosin safety. The study did not reach the estimated power for CYP2D6*3, CYP2D6*6, and CYP2D6*9 polymorphisms due to their low frequency of occurrence in the study population. The multivariate logistic regression model indicated that potential predictors of tamsulosin therapy efficacy in LUTS/BPH patients may include BMI (p<0.001), prostate volume (p<0.002), as well as the carriage of CYP2D6*4 (p<0.001) and CYP2D6*10 (p=0.012) markers. The model explained 81.9 % of the variance in the predicted outcome and accurately forecasted tamsulosin therapy efficacy in BPH with a precision of 92.1 %. The present study identified potential markers that could serve as predictors of the effectiveness of tamsulosin. Specifically, genetic markers such as CYP2D6*4, CYP2D6*10, CYP2D6*41, and non-genetic factors like BMI and prostate volume were associated with the clinical efficacy of tamsulosin therapy in LUTS/BPH patients..
Information about the distribution of clinically significant genetic markers in different populations may be helpful in elaborating personalized approaches to the clinical management of COVID-19 in the absence of consensus guidelines.Analyze frequencies and distribution patterns of two markers associated with severe COVID-19 (rs11385942 and rs657152) and look for potential correlations between these markers and deaths from COVID-19 among populations in Russia and across the world.We genotyped 1883 samples from 91 ethnic groups pooled into 28 populations representing Russia and its neighbor states. We also compiled a dataset on 32 populations from other regions using genotypes extracted or imputed from the available databases. Geographic maps showing the frequency distribution of the analyzed markers were constructed using the obtained data.The cartographic analysis revealed that rs11385942 distribution follows the West Eurasian pattern: the marker is frequent among the populations of Europe, West Asia and South Asia but rare or absent in all other parts of the globe. Notably, the transition from high to low rs11385942 frequencies across Eurasia is not abrupt but follows the clinal variation pattern instead. The distribution of rs657152 is more homogeneous. The analysis of correlations between the frequencies of the studied markers and the epidemiological characteristics of COVID-19 in a population revealed that higher frequencies of both risk alleles correlated positively with mortality from this disease. For rs657152, the correlation was especially strong (r = 0.59, p = 0.02). These reasonable correlations were observed for the "Russian" dataset only: no such correlations were established for the "world" dataset. This could be attributed to the differences in methodology used to collect COVID-19 statistics in different countries.Our findings suggest that genetic differences between populations make a small yet tangible contribution to the heterogeneity of the pandemic worldwide.
The development of highly effective protocols for the treatment of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphomas (NHL) followed the path of escalation of doses of cytostatic agents and improvement of supportive care. Methotrexate (MTX), used in high doses (1000–5000 mg/m 2 ), radically changed the results of treatment of ALL and NHL in children, increasing patient survival rates. The downside of the anti-tumor effect of MTX is its organ toxicity, and therefore the development of methods for predicting the development of toxic effects of MTX is an important scientific and practical task. In recent years, the genetic factors of the patient’s organism have been considered as one of the reasons for the individual variability of pharmacokinetic and pharmacodynamic parameters of MTX. Abnormal function of folate cycle enzymes, methotrexate transporter proteins, due to gene polymorphism, may affect the effectiveness and toxicity of the drug. This review summarizes and analyzes the known genetic polymorphisms involved in MTX metabolism. The possibilities of predicting toxicity, as well as the prospects for individualizing therapy, taking into account the results of pharmacogenetic testing, are presented.
The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods . The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results . Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion . An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.
Significant differences between the gene pools of Russian peoples require the development of ethno- regional adapted pharmacogenetic tests and the identification of priority regions for their implementation. Aim. To develop a genogeographic technology to identify selection effects using the example of biomarkers that are significant for pharmacotherapy of patients with cardiovascular diseases (CVD), using a population biobank and the Pharmacogenetics of Populations of Russia and Adjacent Countries database. Material and methods . Deoxyribonucleic acid (DNA) samples from the Biobank of Northern Eurasia from 20 metapopulations of the indigenous population of the European Russia were studied using two following data sets: 24 pharmacogenetic markers of CVDs (3170 samples); 1 276 191 polymorphic DNA markers of the autosomal genome (1293 samples). For each data set, estimates of interpopulation variability in the gene pool are provided — the difference between these estimates characterizes the selection pressure on each of the 24 CVD biomarkers. A genogeographic atlas has been created, the maps of which demonstrate the selection pressure on each biomarker according to the degree of deviation from the selective- neutral variability of the gene pool. Results. Twenty-four CVD biomarkers are divided into three following classes: those close to selective- neutral variability, those subject to stabilizing and differentiating selection. For each of the 24 CVD biomarkers, genogeographic maps were created that reveal selection effects in each of the 20 metapopulations. Most maps have identified populations that are under differential selection pressure and therefore a priority for the implementation of ethno- regionally adapted pharmacogenetic protocols. Conclusion. Pharmacogenetic markers and populations under differential selection require the development of ethno- regionally adapted pharmacogenetic tests. The created cartographic atlas of selection can serve as the basis for pharmacogenetic studies carried out using genogeographic methods.
Introduction . An outbreak of novel COVID-19 infection has become a real challenge for the entire human society, and first of all for the healthcare services. The development of new drugs is a complex and lengthy process. At the beginning of the pandemic, it forced an intensive study of well-known drugs for the therapy. Remdesivir was first investigated as a potential treatment for Ebola virus. After beginning of the COVID-19 pandemic, in vitro evaluations demonstrated its activity against SARS-CoV-2. Subsequent clinical studies showed the efficacy of remdesivir in shortening the time to recovery. Aim . To evaluate the effect of the carriage of polymorphic alleles of the CES1 gene (A > C, rs2244613) on the safety profile of remdesivir therapy. Materials and methods . A total of 154 patients hospitalized with coronavirus infection were included in the study. All patients received remdesivir as etiotropic therapy in the standard regimen: 200 mg on the first day followed by 100 mg daily for 5-10 days. In the course of observations, clinical and laboratory signs of adverse events were reported. Venous blood samples were collected from each patient for pharmacogenetic studies. Genotyping was performed using the real-time polymerase chain reaction technique. Statistical analysis: вata were analysed by using IBM SPSS Statistics, Version 23.0. Results . There were no significant associations of carriage of various CES1 variants with the frequency of adverse reactions (bradycardia, nausea, vomiting) and laboratory markers of adverse events (ALT, AST, creatinine levels). Conclusion . In our study, no association was found between the carriage of CES1 gene polymorphisms and the safety parameters of remdesivir in hospitalized patients with COVID-19. Further research into the possibilities of personalizing COVID-19 therapy through pharmacogenetic testing is needed.
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