Cartographic atlas of frequency variation for 45 pharmacogenetic markers in populations of Russia and its neighbor states

The lack of information about the frequency of pharmacogenetic markers in Russia impedes the adoption of personalized treatment algorithms originally developed for West European populations. The aim of this paper was to study the distribution of some clinically significant pharmacogenetic markers across Russia. A total of 45 pharmacogenetic markers were selected from a few population genetic datasets, including ADME, drug target and hemostasis-controlling genes. The total number of donors genotyped for these markers was 2,197. The frequencies of these markers were determined for 50 different populations, comprised of 137 ethnic and subethnic groups. A comprehensive pharmacogenetic atlas was created, i.e. a systematic collection of gene geographic maps of frequency variation for 45 pharmacogenetic DNA markers in Russia and its neighbor states. The maps revealed 3 patterns of geographic variation. Clinal variation (a gradient change in frequency along the East-West axis) is observed in the pharmacogenetic markers that follow the main pattern of variation for North Eurasia (13% of the maps). Uniform distribution singles out a group of markers that occur at average frequency in most Russian regions (27% of the maps). Focal variation is observed in the markers that are specific to a certain group of populations and are absent in other regions (60% of the maps). The atlas reveals that the average frequency of the marker and its frequency in individual populations do not indicate the type of its distribution in Russia: a gene geographic map is needed to uncover the pattern of its variation.</jats:p

Do CYP2C19 and ABCB1 gene polymorphisms and low CYP3A4 isoenzyme activity have an impact on stent implantation complications in acute coronary syndrome patients?

Eric Rytkin,1 Karin B Mirzaev,1 Elena A Grishina,1 Valeriy V Smirnov,2 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Michael Iu Giliarov,2 Denis A Andreev,2 Dmitriy A Sychev1 1Russian Medical Academy of Continuous Professional Education, 2I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russian Federation Aim: The aim of this study was to determine the impact of CYP2C19 and ABCB1 gene polymorphisms and CYP3A4 isoenzyme activity on stent implantation complications among patients with an acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI).Patients and methods: Seventy-six patients (median age 63, range 37&ndash;91 years) with an ACS who underwent PCI were screened for CYP2C19 and ABCB1 gene polymorphisms with real-time polymerase chain reaction: CYP2C19*2, CYP2C19*17, and ABCB1 3435. CYP3A4 isoenzyme activity was determined by urine cortisol and 6-beta-hydroxycortisol levels. Stent implantation complications such as stent thrombosis (n=2) and restenosis (n=1) were observed among drug-eluting stent recipients.Results: Low mean 6-beta-hydroxycortisol/cortisol ratio is indicative of impaired CYP3A4 activity and was associated with higher risk of thrombosis (&beta; coefficient=0.022, SE 0.009, p=0.021 in the linear regression model). The increase in the length of the implanted stent was associated with higher risk of restenosis (&beta;&nbsp;coefficient=0.006, SE=0.002, p=0.001 in the linear regression model). The presence of the CYP2C19*2 polymorphism did not affect the incidence of stent thrombosis (&beta;&nbsp;coefficient=&minus;1.626, SE=1.449, p=0.262 in the logistic regression model), nor did the CYP2C19*17 (&beta;&nbsp;coefficient=&minus;0.907, SE=1.438, p=0.528 in the logistic regression model) and ABCB1 3435 polymorphisms (&beta;&nbsp;coefficient=1.270, SE=1.442, p=0.378 in the logistic regression model).Conclusion: We did not find evidence that the presence of CYP2C19*2, CYP2C19*17, and ABCB1 3435 polymorphisms may jeopardize the safety of stent implantation in patients with an ACS. Patients with low CYP3A4 isoenzyme activity may have increased risk of stent thrombosis. Keywords: acute coronary syndrome, clopidogrel, complications, polymorphism, stents&nbsp

Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations

Dmitrij Alekseevitch Sychev,1 Grigorij Nikolaevich Shuev,1 Salavat Shejhovich Suleymanov,2 Kristina Anatol&rsquo;evna Ryzhikova,3 Karin Badavievich Mirzaev,3 Elena Anatol&rsquo;evna Grishina,3 Natalia Evgenievna Snalina,3 Zhannet Alimovna Sozaeva,3 Anton Mikhailovich Grabuzdov,4 Irina Andreevna Matsneva4 1Department of Internal Medicine and Clinical Pharmacology, Russian Medical Academy of Continuing Professional Education, Ministry of Healthcare, Moscow, 2Saiko Russian&ndash;Japanese Medical Center, Khabarovsk, 3Research Centre, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, 4Department of General Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation Background: The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. Materials and methods: We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data. Results: After performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy&ndash;Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians. Conclusion: In the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of Russia. Keywords: pharmacogenetics, ethnicity, Asians, Europeans, SNP, P450 cytochrome, ethnic group, P-glycoprotei

The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty

Dmitriy Alekseevich Sychev,1 Alexander Nikolaevich Levanov,2 Tatiana Vladimirovna Shelekhova,2 Pavel Olegovich Bochkov,3 Natalia Pavlovna Denisenko,4 Kristina Anatolyevna Ryzhikova,4 Karin Badavievich Mirzaev,3 Elena Anatolyevna Grishina,4 Mikhail Alekseevich Gavrilov,5 Galina Vladislavovna Ramenskaya,6 Aleksei Vladimirovich Kozlov,6 Tanya Bogoslovsky7 1Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2Department of Occupational Pathology, Haematology and Clinical Pharmacology, Saratov State Medical University named after V.I. Razumovsky, Saratov, Russia; 3Department of Personalized Medicine, Research Center, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 4Department of Molecular Medicine, Research Center, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 5Department of Traumatology and Orthopedics, Research Institute of Traumatology, Orthopedics and Neurosurgery, Saratov State Medical University named after V.I. Razumovsky, Saratov, Russia; 6Department of A.P. Arzamastsev Pharmaceutical and Toxicological Chemistry, Sechenov First Moscow Medical State University, Moscow, Russia; 7Department of Neurology, Division of Clinical Neurosciences, Turku University&nbsp;Hospital, Turku, Finland Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37&ndash;81&nbsp;years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220&nbsp;mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p&lt;0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations. Keywords: new oral anticoagulants, dabigatran, venous thromboembolism, ABCB1, CES1, pharmacogenetic

CYP2C19 polymorphism frequency in Russian patients in Central Russia and Siberia with acute coronary syndrome

Karin B Mirzaev,1 Elena M Zelenskaya,2 Olga L Barbarash,3 Vladimir I Ganyukov,3 Konstantin A Apartsin,4,5 Natalya O Saraeva,4 Konstantin Y Nikolaev,6,7 Kristina A Ryzhikova,1 Galina I Lifshits,2,5,7 Dmitry A Sychev1 1Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow, 2Federal State-Financed Research Institution &ldquo;Institute of Chemical Biology and Fundamental Medicine&rdquo;, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 3Federal State-Financed Research Institution &ldquo;Research Institute for Complex Issues of Cardiovascular Diseases&rdquo;, Siberian Branch of the Russian Academy of Sciences, Kemerovo, 4State-Financed Health Institution &ldquo;Irkutsk Regional Badge of Honour Clinical Hospital&rdquo;, 5Federal State-Financed Research Institution &ldquo;Irkutsk Research Center&rdquo;, Siberian Branch of the Russian Academy of Sciences, Irkutsk City, 6Federal State-Financed Research Institution &ldquo;Research Institute of Internal and Preventive Medicine&rdquo;, 7Federal State Autonomous Institution of Higher Education &ldquo;Novosibirsk National Research State University&rdquo;, Novosibirsk, Russia Purpose: The aim of this study is to investigate the frequency of CYP2C19*2, *3 allelic variants, associated with poor response to clopidogrel, and CYP2C19*17, associated with excessive response to clopidogrel, in patients with acute coronary syndrome (ACS) from Siberia and Moscow regions of Russia.Patients and methods: The study included 512 ACS patients who were subsequently treated with coronary arterial stenting. The subjects assigned were from the cities of Central (Novosibirsk, Kemerovo), Eastern (Irkutsk), Northern (Surgut) Siberia regions and from Moscow region. The mean age of patients enrolled was 63.9&plusmn;10.9 years. Among the assigned subjects, the proportion of men accounted for 80% and women 20%.Results: According to the results obtained in the present study, from 16% up to 27.5% of patients in different regions of Russia have at least one CYP2C19 &ldquo;poor metabolizer&rdquo; (PM) allele variant affecting clopidogrel metabolism and, therefore, suppressing its antiplatelet activity. CYP2C19*17 allele variant was identified with the frequency of 15.4% up to 33.3%. The study revealed the presence of statistically significant differences in CYP2C19*3 allele frequency between the Russian ethnic group patients from Eastern and Central Siberia (p=0.001; odds ratio=1.05 [95% confidence interval 1.01&ndash;1.09]).Conclusion: The study revealed statistically significant differences between the allele frequencies in Eastern and Central Siberia, which can probably be caused by a considerable number of Buryats inhabiting Eastern Siberia. Keywords: P2Y12 receptor inhibitors, clopidogrel resistance, dual antiplatelet therap