The CES1 Gene rs2244613 Minor Allele Impact on the Safety Profile of Dabigatran Etexilate: Meta-Analysis

Aim. A meta-analysis of studies on the CES1 gene c.1168-33A>C polymorphism (rs2244613) carriage influence on the equilibrium concentration and the risk of bleeding during dabigatran taking.Material and methods. The search was carried out in the Russian Science Citation Index, Google Academy, Medline PubMed, Embase databases. The meta-analysis included patients who according to the indications (atrial fibrillation, stroke, joint orthopedic surgery) were prescribed dabigatran in various doses. The association was identified in rs2244613 allele C carriers (genotypes AC and CC) and non-carriers (genotype AA). Quantitative synthesis was performed using OpenMetaAnalyst software. In statistical analysis the fixed effects model was used to estimate the influence of the allele C carriage on the any bleeding frequency and the random effects model was used to estimate the influence on the equilibrium plasma concentration level of dabigatran. The homogeneity of the analyzed studies was verified by Cochrane Q-test.Results. The analysis resulted in selection of 5 works matching all meta-analysis inclusion/exclusion criteria. All selected works included 2030 patients in total. The carriage of the rs2246613 allele C was associated with reduction of risk of any bleeding during dabigatran taking (risk ratio [RR] 0.732, 95% confidence interval [CI] 0.629-0.851; p<0.001). The heterogeneity test did not reveal any reliable differences between the study results (Q=2.183; p=0.535). The level of equilibrium residual concentration of dabigatran was not statistically significant lower for the carriers of C allele of the rs2244613 (mean difference -69.324, 95%CI -236.687-98.039; p=0.417). This might be related to the small sample size and the number of studies included in the meta-analysis. The heterogeneity test did not reveal statistically significant differences between studies (Q=0.388; I2=0%, p=0.534).Conclusion. The carriage of minor C allelic variant of rs2244613 reduces the risk of any bleeding during dabigatran taking, however, no significant association with decrease in dabigatran concentration was found.

Effects of the rs2244613 polymorphism of the CES1 gene on the antiplatelet effect of the receptor P2Y12 blocker clopidogrel

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.

Comparative clinical and economic evaluation of pharmacogenetic testing application for dabigatran in patients with atrial fibrillation

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.

Multi-Ethnic Analysis of Cardiac Pharmacogenetic Markers of Cytochrome P450 and Membrane Transporters Genes in the Russian Population

Aim. To summarize Russian studies using pharmacogenetic testing as applied to cardiology.Material and methods. The authors conducted an online search for articles in December 2018 using the following databases: PubMed, Google Scholar, eLIBRARY. The search was carried out by keywords: "Russia", "Russian", "cardiology" together with the terms associated with the polymorphic marker, including: «P450», «CYP2C19», «CYP2D6», «CYP2B1», «CYP2B6», «CYP2Е1», «CYP2C8», «CYP2C9», «CYP3A4», «CYP3A5», «CYP1A1», «CYP1A2», «CYP4F2», «CYP4F1», «ABCB1», «SLCO1B1», «VKORC1», «GGCX», «SULT1A1», «CULT1», «CES1», «gene», «genes», «pharmacogenetics», «pharmacogenomics», «ethnic group».Results. Generalization of information allowed to identify obscure genes that need to be investigated in pharmacogenetic studies. This information can be used for the development of dosing algorithms and the priority choice of drugs, considering the results of pharmacogenetic testing and planning future research.Conclusion. The results of the literature review indicate the importance of studying the most clinically valid and clinically useful pharmacogenetic markers (CYP2C19, CYP2C9, VKORC1, SLCO1B1) among various ethnic groups in the Russian Federation. With the accumulation of evidence of clinical validity and clinical utility of other pharmacogenetic markers (CES1, CYP2D6*4, etc.), the problem of interethnic differences in the carriage of clinically significant polymorphisms of these genes identified in previous studies in the Russian Federation increasingly requires attention. The most promising for the introduction into the clinical practice in the Russian Federation in the near future are polymorphic markers of the CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes.