Genetic determinants of dabigatran safety (CES1 gene rs2244613 polymorphism) in the Russian population: multi-ethnic analysis

  • Dmitry Alekseevich Sychev
  • Sherzod Pardaboevich AbdullaevEmail author
  • Karin Badavievich Mirzaev
  • Kristina Anatolevna Ryzhikova
  • Grigoriy Nikolaevich Shuyev
  • Zhannet Alimovna Sozaeva
  • Elena Anatolevna Grishina
  • Suleiman Nurattinovich Mammaev
  • Daniyal Musaevich Gafurov
  • Elena Yurievna Kitaeva
  • Vladimir Viktorovich Shprakh
  • Salavat Sheikhovich Suleymanov
  • Laura Zelimkhanovna Bolieva
  • Maryam Sultan-Hamitovna Sozaeva
  • Svetlana Mikhailovna Zhuchkova
  • Natalia Evgenievna Gimaldinova
  • Elena Eduardovna Sidukova
  • Anastasiia Valerievna Asoskova
  • Robert Borisovich Mumladze
Original Article


This study was aimed to investigate the prevalence of the CES1 gene (c.1168-33A > C, rs2244613) polymorphism among 12 different ethnic groups living in Russia to provide a basis for future clinical studies concerning genetic determinants of dabigatran safety. The study involved 1630 apparently healthy, unrelated, and chronic medication-free volunteers of both genders from 12 different ethnic groups in Russia: 136 Russians, 90 Avars, 50 Dargins, 46 Laks, 120 Kabardians, 112 Balkars, 244 Ossetians, 206 Mari, 204 Mordvinians, 238 Chuvashes, 114 Buryats and 70 Nanays. Genotyping was performed by using real-time polymerase chain reaction-based methods. The allelic prevalence of the ethnic groups was compared with Caucasus population participating in the RE-LY study. Statistically significant differences for the following gene polymorphism were found between all ethnic groups and RE-LY participants. Based on obtained results, it can be assumed that patients of all ethnic groups living in Russia taking dabigatran have a lower risk of bleeding.


CES1 Rs2244613 Dabigatran Ethnicity Pharmacogenetics 



The funding organization played no role in the study design, in the collection, analysis, and interpretation of data as well as in the writing of the article and in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

The work was carried out with the financial support of OOO Boehringer Ingelheim (Moscow, Russian Federation). All the authors report no conflicts of interest in this work.


  1. 1.
    Alwan A (2011) Global status report on noncommunicable diseases 2010 Introduction. In: A. Alwan, editor. Global status report on noncommunicable diseases 2010. World Health Organization, Geneva. pp VII–IX. Accessed 26 Aug 2018
  2. 2.
    World Health Organization website. Accessed 26 Aug 2018
  3. 3.
    Goldhaber SZ, Bounameaux H (2012) Pulmonary embolism and deep vein thrombosis. Lancet 379(9828):1835–1846. CrossRefGoogle Scholar
  4. 4.
    Napalkov DA, Sokolova AA, Rodionov AV (2016) Atrial fibrillation and ischemic heart disease: how to combine antiplatelet and anticoagulant therapy, depending on the clinical situation? Ration Pharmacother Cardiol 2(21):191–195. (In Russ)CrossRefGoogle Scholar
  5. 5.
    Kirchhof P, Benussi S, Kotecha D et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 50(5):1–88. CrossRefGoogle Scholar
  6. 6.
    Ross S, Pare G (2013) Pharmacogenetics of antiplatelets and anticoagulants: a report on clopidogrel, warfarin and dabigatran. Pharmacogenomics 14(13):1565–1572. CrossRefGoogle Scholar
  7. 7.
    Sychev DA, Kazakov RE, Otdelenov VA, Prokofiev AB (2013) Applications of pharmacogenetic testing for personalization of therapy with oral anticoagulants in Russia. Ration Pharmacother Cardiol 9(5):525–531. CrossRefGoogle Scholar
  8. 8.
    Eriksson N, Wadelius M (2012) Prediction of warfarin dose: why, when and how? Pharmacogenomics 13(4):429–440. CrossRefGoogle Scholar
  9. 9.
    Johnson JA (2008) Ethnic differences in cardiovascular drug response: potential contribution of pharmacogenetics. Circulation 118(13):1383–1393. CrossRefGoogle Scholar
  10. 10.
    Mazur-Bialy AI, Zdebska K, Wypasek E, Undas A (2013) Repeated bleeding complications during therapy with vitamin K antagonists in a patient with the VKORC1*2A and the CYP2C9*3/*3 alleles: genetic testing to support switching to new oral anticoagulants. Thromb Res 131(3):279–280. CrossRefGoogle Scholar
  11. 11.
    Blech S, Ebner T, Ludwig-Schwellinger E et al (2008) The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 36:386–399. CrossRefGoogle Scholar
  12. 12.
    Stangier J, Eriksson BI, Dahl OE et al (2005) Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 45:555–563. CrossRefGoogle Scholar
  13. 13.
    Shi J, Wang X, Nguyen JH, Bleske BE et al (2016) Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol 119:76–84. CrossRefGoogle Scholar
  14. 14.
    Zhu HJ, Wang X, Gawronski BE et al (2013) Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther 344:665–672. CrossRefGoogle Scholar
  15. 15.
    Shi J, Wang X, Eyler RF et al (2016) Association of oseltamivir activation with gender and carboxylesterase 1 genetic polymorphisms. Basic Clin Pharmacol Toxicol 199:555–561. CrossRefGoogle Scholar
  16. 16.
    Nemoda Z, Angyal N, Tarnok Z et al (2009) Carboxylesterase 1 gene polymorphism and methylphenidate responsein ADHD. Neuropharmacology 57:731–733. CrossRefGoogle Scholar
  17. 17.
    Wang X, Wang G, Shi J et al (2016) CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors. Pharmacogenomics J 16:220–230. CrossRefGoogle Scholar
  18. 18.
    Tarkiainen EK, Tornio A, Holmberg MT et al (2015) Effect of carboxylesterase 1 c.428G> A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol 80:1131–1138CrossRefGoogle Scholar
  19. 19.
    Hamzic S, Kummer D, Milesi S et al (2017) Novel genetic variants in carboxylesterase 1 predict severe early onset capecitabine-related toxicity. Clin Pharmacol Ther 102(5):796–804. CrossRefGoogle Scholar
  20. 20.
    Merali Z, Ross S, Pare G (2014) The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact 29(3):143–151. CrossRefGoogle Scholar
  21. 21.
    Rasmussen HB, Bjerre D, Linnet K et al (2015) Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics. Pharmacogenomics 16(6):649–665. CrossRefGoogle Scholar
  22. 22.
    Jackson LR, Peterson ED, Okeagu E, Thomas K (2015) Review of race/ethnicity in non-vitamin K antagonist oral anticoagulants clinical trials. J Thromb Thrombolysis 39(2):222–227. CrossRefGoogle Scholar
  23. 23.
    Tang H, Quertermous T, Rodriguez B et al (2005) Genetic Structure, Self-Identified Race/Ethnicity, and Confounding in Case-Control Association Studies. Am J Hum Genet 76(2):268–275. CrossRefGoogle Scholar
  24. 24.
    Pare G, Eriksson N, Lehr T et al (2013) Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127:1404–1412. CrossRefGoogle Scholar
  25. 25.
    PharmGKB website: Accessed 1 Sept 2018
  26. 26.
    Caciagli L, Bulayeva K, Bulayev O et al (2009) The key role of patrilineal inheritance in shaping the genetic variation of Dagestan highlanders. J Hum Genet 54(12):689–694. CrossRefGoogle Scholar
  27. 27.
    Yunusbayev B, Kutuev I, Khusainova R et al (2006) Genetic structure of Dagestan populations: a study of 11 Alu insertion polymorphisms. Hum Biol 78(4):465–476. CrossRefGoogle Scholar
  28. 28.
    Mirzaev KB, Sychev DA, Ryzhikova KA et al (2017) Genetic polymorphisms of cytochrome P450 enzymes and transport proteins in a Russian population and three ethnic groups of Dagestan. Genet Test Mol Biomarkers 21(12):747–753. CrossRefGoogle Scholar
  29. 29.
    Balanovsky OP (2017) Gene pool of Europe. The Partnership of Scientific Publications, Moscow (In Russ.)Google Scholar
  30. 30.
    Gu ZC, Ma XW, Zheng XY et al (2018) Left atrial appendage thrombus formation in a patient on dabigatran therapy associated with ABCB1 and CES-1 genetic defect. Front Pharmacol 9:491. CrossRefGoogle Scholar
  31. 31.
    Golukhova EZ, Grigoryan MV, Ryabinina MN (2014) Modern aspects of clopidogrel pharmacogenetics and its clinical relevance. Creat Cardiol 3:39–52. (In Russ.)Google Scholar
  32. 32.
    Rehman KU, Akhtar T, Sabar MF, Tariq MA (2015) Allele frequency distribution of CYP2C19*2 allelic variants associated with clopidogrel resistance in cardiac patients. Exp Ther Med 10(1):309–315. CrossRefGoogle Scholar
  33. 33.
    Sukasem C, Tunthong R, Chamnanphon M et al (2013) CYP2C19 polymorphisms in the Thai population and the clinical response to clopidogrel in patients with atherothrombotic-risk factors. Pharmgenomics Pers Med 6:85–91. Google Scholar
  34. 34.
    Sychev DA, Shuev GN, Suleymanov SS et al (2017) Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB12017, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations. Pharmgenomics Pers Med 10:93–99. Google Scholar
  35. 35.
    Romodanovsky DP, Khapaev BA, Ignatiev IV et al (2010) Frequencies the «slow» allele variants of the genes coding isoenzymes of cytochrome Р450 CYP2D6, CYP2C19, CYP2C9 in Karachaevs and Circassians. Biomedicine 2:33–37 (In Russ.)Google Scholar
  36. 36.
    Dager WE, Banares L (2017) Reversing the anticoagulation effects of dabigatran. Hosp Pract 45(2):29–38. CrossRefGoogle Scholar
  37. 37.
    NCBI website: Accessed 14 Sept 2018
  38. 38.
    Baker WL, Johnson SG (2016) Pharmacogenetics and oral antithrombotic drugs. Curr Opin Pharmacol 27:38–42. CrossRefGoogle Scholar
  39. 39.
    Dimatteo C, D’Andrea G, Vecchione G et al (2016) Pharmacogenetics of dabigatran etexilate interindividual variability. Thromb Res 144:1–5. CrossRefGoogle Scholar
  40. 40.
    Sychev DA, Levanov AN, Shelekhova TV et al (2018) The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty. Pharmgenomics Pers Med 11:127–137. Google Scholar
  41. 41.
    Reilly PA, Lehr T, Haertter S et al (2014) The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long Term Anticoagulation Therapy). J Am Coll Cardiol 63:321–328. CrossRefGoogle Scholar
  42. 42.
    Eriksson BI, Dahl OE, Buller HR et al (2005) A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 3:103–111. CrossRefGoogle Scholar
  43. 43.
    Chin PK, Wright DF, Zhang M et al (2014) Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C. Drugs R D 14(2):113–123. CrossRefGoogle Scholar
  44. 44.
    Mirzaev KB, Osipova DV, Kitaeva EYu et al (2018) CES1 gene polymorphism effect on the antiplatelet activity of clopidogrel. Clin Pharmacol Ther 27(5):96–100. (In Russ)CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Dmitry Alekseevich Sychev
    • 1
  • Sherzod Pardaboevich Abdullaev
    • 1
    Email author
  • Karin Badavievich Mirzaev
    • 1
  • Kristina Anatolevna Ryzhikova
    • 1
  • Grigoriy Nikolaevich Shuyev
    • 1
  • Zhannet Alimovna Sozaeva
    • 1
  • Elena Anatolevna Grishina
    • 1
  • Suleiman Nurattinovich Mammaev
    • 2
  • Daniyal Musaevich Gafurov
    • 3
  • Elena Yurievna Kitaeva
    • 4
  • Vladimir Viktorovich Shprakh
    • 4
  • Salavat Sheikhovich Suleymanov
    • 5
  • Laura Zelimkhanovna Bolieva
    • 6
  • Maryam Sultan-Hamitovna Sozaeva
    • 7
  • Svetlana Mikhailovna Zhuchkova
    • 8
  • Natalia Evgenievna Gimaldinova
    • 9
  • Elena Eduardovna Sidukova
    • 10
  • Anastasiia Valerievna Asoskova
    • 1
  • Robert Borisovich Mumladze
    • 1
  1. 1.Federal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of Continuous Professional Education” of the Ministry of Healthcare of the Russian FederationMoscowRussian Federation
  2. 2.Federal State Budgetary Educational Institution of Higher Education “Dagestan State Medical University” of the Ministry of Healthcare of the Russian FederationMakhachkalaRussian Federation
  3. 3.State Budgetary Institution of the Republic of Dagestan “Laksky Central District Hospital”MakhachkalaRussian Federation
  4. 4.Irkutsk State Medical Academy of Postgraduate Education – Branch Campus of the Federal State Budgetary Educational Institution of Further Professional Education “Russian Medical Academy of of Continuous Professional Education” of the Ministry of Healthcare of the Russian FederationIrkutskRussian Federation
  5. 5.Saiko Russian-Japanese Medical CenterKhabarovskRussian Federation
  6. 6.Federal State Budgetary Educational Institution of Higher Education “North Ossetia State Medical Academy” of the Ministry of Healthcare of the Russian FederationVladikavkazRussian Federation
  7. 7.State Budgetary Healthcare Institution “Republican Clinical Hospital” of the Ministry of Healthcare of the Russian FederationNalchikRussian Federation
  8. 8.Autonomous Institution “Republican Clinical Oncologic Dispensary” of the Ministry of Health of the Chuvash RepublicCheboksaryRussian Federation
  9. 9.Federal State Budgetary Educational Institution of Higher Education “I. N. Ulianov Chuvash State University”CheboksaryRussian Federation
  10. 10.State Budgetary Institution of the Republic of Mari El “Kozmodemyansk Interdistrict Hospital”KozmodemyanskRussian Federation

Personalised recommendations