Aim: The aim of this study is to assess 6 micro-RNAs: miR-126, miR-223, miR-150, miR-29, miR-34, miR-142 as potential biomarkers for P2Y12- inhibitors resistance prediction. Methods: Eighty patients with an acute coronary syndrome undergoing percutaneous coronary intervention treated in a multidisciplinary hospital in Moscow with DAPT (either with ticagrelor, n=45, or clopidogrel, n=35) were enrolled. The carriership of 6 clinically relevant polymorphisms for ticagrelor and 17 for clopidogrel was detected. Expression levels of six prospective miRNAs were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of cortisol and 6β-hydroxycortisol. Results: The polymorphisms of the P2Y12-inhibitors ADME genes that demonstrated statistically significant connection with miRNA expression levels are as follows: P2Y12R (A>G, rs3732759) and miR-29 (p=0.017), miR-34 (p=0.003); CYP2C19*17 (C-806T, rs1224856) and miR-142 (p=0.012); PON1 (Q192R, rs662) and miR-29 (p=0.004), ABCG2 (G>T, rs2231142) and miR-34 (p=0.007). MiRNAs expression levels showed connection with the results of the platelet reactivity assessment by utilizing VerifyNow assay (“Instrumentation laboratory”, MA, US). MiR-126 (β coefficient=− 0.076, SE=0.032, p=0.021), miR-223 (β coefficient=− 0.089, SE=0.041, p=0.032), miR-29 (β coefficient=− 0.042, SE=0.018, p=0.026), miR-142 (β coefficient=− 0.072, SE=0.026, p=0.008) have the potential to be used as biomarkers and may substitute platelet reactivity testing. Conclusion: This study has revealed new biomarkers for P2Y12-inhibitors resistance testing: miR-29, miR-34, miR-126, miR-142, miR-223.

Background: The aim of this study was to evaluate the association of the carriage of the rs2244613 polymorphism of the CES1 gene with clopidogrel resistance as well as to evaluate the effectiveness of antiplatelet therapy in the carriers of this marker who have had acute coronary syndrome (ACS). This study also analyzes the procedure of percutaneous coronary intervention and compares the rs2244613 carrier rate between patients with ACS and healthy participants. Methods: The study involved 81 patients diagnosed with ACS and 136 conditionally healthy participants. The optical detection of platelet agglutination by VerifyNow was employed to measure residual platelet reactivity in patients with ACS. The rs2244613 polymorphism was determined using real-time polymerase chain reaction. Results: According to the results, the AA genotype of the rs2244613 polymorphism of the CES1 gene was detected in 37 patients (45.6%), the CA genotype in 42 patients (51.8%) and the CC genotype in 2 patients (2.6%). The level of residual platelet reactivity in rs2244613 carriers was higher compared with patients who did not have this allelic variant: 183.23 PRU ± 37.24 vs. 154.3 PRU ± 60.36 (p = 0.01). The frequencies of the minor allele C were 28.4% and 28.3% in patients with ACS and healthy participants, respectively. The results of the linear statistical model PRU due to CES1 genotype were as follows: df = 1, F = 6.96, p = 0.01). The standardized beta was 0.285 (p = 0.01) and R² was 0.081. However, we also added CYP2C19*2 and *17 into the linear regression model. The results of the model were as follows: df = 3, F = 5.1, p = 0.003) and R² was 0.166. Conclusions: We identified a statistically significant correlation between the carriage of the rs2244613 polymorphism of the CES1 gene and the level of residual platelet aggregation among patients with ACS and the procedure of percutaneous coronary intervention.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 ± 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326–5.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17–3.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug–drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban.

Aim. To evaluate the clinical and economic feasibility of pharmacogenetic testing (PGT) for dabigataran etexilate administration in the treatment of atrial fibrillation (AF) without valve in comparison with tactics without pharmacogenetic testing. Materials and methods. The pharmacoeconomic model was done using generalized data from published clinical, epidemiological and clinical-economic studies. Results and discussion. Application of PGT on the carrier of allelic variant rs2244613 of CES1 gene for adjustment of dabigatrane etexilate dosage in patients with non-valve AF may be more cost-effective strategy for prevention of thromboembolic complications in patients with non-valve AF. Thus, due to the decrease in the number of undesirable drug reactions in the form of minor and major bleedings, the difference in treatment costs in the group with PGT compared to the group with standard pharmacotherapy tactics per 100 patients was 11 827.65 rubles. The expected cost per patient per year for standard treatment was 36 051.35 rubles, while in the group with PGT it was 35 933.07 rubles. The difference was 1182.76 rubles in favor of the pharmacogenetic approach Conclusion. A PGT approach to correct dabigatrane dosage can reduce the cost of pharmacotherapy by reducing the risk of adverse reactions of minor and major bleeding. Keywords: dabigatran, pharmacoeconomics, pharmacogenetic testing, CES1