Molecular Biology Reports

, Volume 46, Issue 2, pp 1825–1833 | Cite as

Interpretation of the effect of CYP2C9, VKORC1 and CYP4F2 variants on warfarin dosing adjustment in Turkey

  • Ahmet Kocael
  • Allison Pınar Eronat
  • Mete Bora Tüzüner
  • Ahmet Ekmekçi
  • Ahmet Lütfullah Orhan
  • İbrahim İkizceli
  • Hülya Yılmaz-Aydoğan
  • Oğuz ÖztürkEmail author
Original Article


It was aimed to underline the importance and explain the meaning of genetic testing in warfarin dosing and investigate and evaluate the contributions of the CYP2C9, VKORC1, and CYP4F2 variants in a Turkish population. Two hundred patients were genotyped for CYP2C9 (rs1799853, rs1057910 and rs56165452), VKORC1 (rs9934438, rs8050894, rs9923231, rs7294 and rs2359612) and CYP4F2 (rs2108622), yet, only 127 patients were found suitable for further evaluation in terms of their personal response to warfarin due to long term usage and available INR and dose usage information. The DNA sequences were determined by the ABI PRISM 3100 Genetic Analyzer to 3130xl System (Applied Biosystems, Foster City, California). Warfarin dose application suggestions by, FDA and MayoClinic were followed. Dose requirements in the Turkish population were found higher than the suggested doses by The multivariate logistic regression analysis reveals the utilization of VCORC1 genetic evaluation is valuable in warfarin dosing (low and moderate vs. high) in this study (p < 0.001). The present study provides findings for clinicians to adapt the genetic data to the daily practice. We observed that the VKORC1 variant showed a more potent impact in warfarin dosing in this study.


Warfarin dosing Drug sensitivity Pharmacogenetics 



This study was funded by the Scientific Research Projects Unit of Istanbul University (I.U. BAP Project No: 28968).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no any financial or non-financial conflict of interests.


  1. 1.
    Hocum BT, White JR Jr, Heck JW, Thirumaran RK, Moyer N, Newman R, Ashcraft K (2016) Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. Am J Health Syst Pharm 73:61–67. CrossRefPubMedGoogle Scholar
  2. 2.
    Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690–1698CrossRefPubMedGoogle Scholar
  3. 3.
    Tie JK, Stafford DW (2016) Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost 14:236–247. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tian L, Zhang J, Xiao S, Huang J, Zhang Y, Shen J (2015) Impact of polymorphisms of the GGCX gene on maintenance warfarin dose in Chinese populations: systematic review and meta-analysis. Meta Gene 5:43–54. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hamadeh IS, Shahin MH, Lima SM, Oliveira F, Wilson L, Khalifa SI, Langaee TY, Cooper-DeHoff RM, Cavallari LH, Johnson JA (2016) Impact of GGCX, STX1B and FPGS polymorphisms on Warfarin dose requirements in European-Americans and Egyptians. Clin Transl Sci 9:36–42. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Li T, Lange LA, Li X, Susswein L, Bryant B, Malone R, Lange EM, Huang TY, Stafford DW, Evans JP (2006) Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 43:740–744CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Flora DR, Rettie AE, Brundage RC, Tracy TS (2017) CYP2C9 genotype-dependent warfarin pharmacokinetics: impact of CYP2C9 genotype on R- and S-Warfarin and their oxidative metabolites. J Clin Pharmacol 57:382–393. CrossRefPubMedGoogle Scholar
  8. 8.
    Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293CrossRefPubMedGoogle Scholar
  9. 9.
    Schalekamp T, Brassé BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, van Wijk EM, Egberts AC, de Boer A (2006) VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 80:13–22CrossRefPubMedGoogle Scholar
  10. 10.
    Cavallari LH, Duarte JD (2015) Genes affecting warfarin response-interactive or additive? J Clin Pharmacol 55:258–260. CrossRefPubMedGoogle Scholar
  11. 11.
    Epstein RS, Moyer TP, Aubert RE, O’Kane DJ, Xia F, Verbrugge RR, Gage BF, Teagarden JR (2010) Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 55:2804–2812. CrossRefPubMedGoogle Scholar
  12. 12.
    Budnitz DS, Lovegrove MC, Shehab N, Richards CL (2011) Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 365:2002–2012. CrossRefPubMedGoogle Scholar
  13. 13.
    Eckman MH, Rosand J, Greenberg SM, Gage BF (2009) Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 150:73–83CrossRefPubMedGoogle Scholar
  14. 14.
  15. 15.
    Saffian SM, Duffull SB, Wright DF (2017) Warfarin dosing algorithms underpredict dose requirements in patients requiring ≥ 7 mg daily: a systematic review and meta-analysis. Clin Pharmacol Ther 102:297–304. CrossRefPubMedGoogle Scholar
  16. 16.
    McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE (2009) CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol 75:1337–1346. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zeng WT, Xu Q, Li CH, Chen WY, Sun XT, Wang X, Yang YY, Shi H, Yang ZS (2016) Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese. Eur J Clin Pharmacol 72:1327–1334CrossRefPubMedGoogle Scholar
  18. 18.
    Özer M, Demirci Y, Hizel C, Sarikaya S, Karalti İ, Kaspar Ç, Alpan S, Genç E (2013) Impact of genetic factors (CYP2C9, VKORC1 and CYP4F2) on warfarin dose requirement in the Turkish population. Basic Clin Pharmacol Toxicol 112:209–214. CrossRefPubMedGoogle Scholar
  19. 19.
    Karaca S, Bozkurt NC, Cesuroglu T, Karaca M, Bozkurt M, Eskioglu E, Polimanti R (2015) International warfarin genotype-guided dosing algorithms in the Turkish population and their preventive effects on major and life-threatening hemorrhagic events. Pharmacogenomics 16:1109–1118. CrossRefPubMedGoogle Scholar
  20. 20.
    World Medical Association (2013) World Medical Association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194CrossRefGoogle Scholar
  21. 21.
  22. 22.
  23. 23.
    Lindh JD, Holm L, Andersson ML, Rane A (2009) Influence of CYP2C9 genotype on warfarin dose requirements—a systematic review and meta-analysis. Eur J Clin Pharmacol 65:365–375CrossRefPubMedGoogle Scholar
  24. 24.
    Inoue H, Nozawa T, Hirai T, Goto S, Origasa H, Shimada K et al (2010) Sex-related differences in the risk factor profile and medications of patients with atrial fibrillation recruited in J-TRACE. Circ J 74:650–654CrossRefPubMedGoogle Scholar
  25. 25.
    Marsh S, McLeod HL (2006) Pharmacogenomics: from bedside to clinical practice. Hum Mol Genet 15(Spec No 1):R89–R93CrossRefPubMedGoogle Scholar
  26. 26.
  27. 27.
    Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG et al (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:975–983. CrossRefPubMedGoogle Scholar
  28. 28.
    Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG et al (2008) Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 118:2029–2037. CrossRefPubMedGoogle Scholar
  29. 29.
    van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VH et al (2017) Implementing pharmacogenomics in Europe: design and implementation strategy of the ubiquitous pharmacogenomics consortium. Clin Pharmacol Ther 101:341–358. CrossRefPubMedGoogle Scholar
  30. 30.
    Haga SB, Moaddeb J, Mills R, Voora D (2017) Assessing feasibility of delivering pharmacogenetic testing in a community pharmacy setting. Pharmacogenomics 18:327–335.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Stanek EJ, Sanders CL, Taber KA, Khalid M, Patel A, Verbrugge RR et al (2012) Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin Pharmacol Ther 91:450–458. CrossRefPubMedGoogle Scholar
  32. 32.
    Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–263CrossRefPubMedGoogle Scholar
  33. 33.
    Kirchheiner J, Brockmöller J (2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 77:1–16CrossRefPubMedGoogle Scholar
  34. 34.
    Aynacioglu AS, Brockmöller J, Bauer S, Sachse C, Güzelbey P, Ongen Z, Nacak M, Roots I (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415CrossRefPubMedGoogle Scholar
  35. 35.
    Babaoglu MO, Yasar U, Sandberg M, Eliasson E, Dahl ML, Kayaalp SO, Bozkurt A (2004) CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur J Clin Pharmacol 60:337–342PubMedGoogle Scholar
  36. 36.
    Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, Siva A, Saip S, Johnson JA (2008) VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 64:889–894. CrossRefPubMedGoogle Scholar
  37. 37.
    Imai J, Ieiri I, Mamiya K, Miyahara S, Furuumi H, Nanba E et al (2000) Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics 10:85–89CrossRefPubMedGoogle Scholar
  38. 38.
    Yang L, Ge W, Yu F, Zhu H (2010) Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement—a systematic review and meta analysis. Thromb Res 125:e159–e166. CrossRefPubMedGoogle Scholar
  39. 39.
    D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649CrossRefPubMedGoogle Scholar
  40. 40.
    Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG et al (2006) Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 16:101–110CrossRefPubMedGoogle Scholar
  41. 41.
    Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Saito S et al (2006) Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet 51:249–253CrossRefPubMedGoogle Scholar
  42. 42.
  43. 43.
    Crosier MD, Peter I, Booth SL, Bennett G, Dawson-Hughes B, Ordovas JM (2009) Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylase genes with biochemical measures of vitamin K status. J Nutr Sci Vitaminol (Tokyo) 55:112–119CrossRefGoogle Scholar
  44. 44.
    Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA et al (2017) Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clin Pharmacol Ther 102:397–404. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Alvarellos ML, Sangkuhl K, Daneshjou R, Whirl-Carrillo M, Altman RB, Klein TE (2015) PharmGKB summary: very important pharmacogene information for CYP4F2. Pharmacogenet Genomics 25:41–47. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P et al (2008) CYP4F2 genetic variant alters required warfarin dose. Blood 111:4106–4112. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Çelik A, İzci S, Kobat MA, Ateş AH, Çakmak A, Çakıllı Y, Yılmaz MB, Zoghi M, WARFARIN-TR Study Collaborates (2016) The awareness, efficacy, safety, and time in therapeutic range of warfarin in the Turkish population: WARFARIN-TR. Anatol J Cardiol 16:595–600. CrossRefPubMedGoogle Scholar
  48. 48.
    Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ (2005) Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 91:472–477CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of General Surgery, Cerrahpasa Medical FacultyIstanbul UniversityIstanbulTurkey
  2. 2.Department of Molecular Medicine, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
  3. 3.Research and Development CenterAcibadem Labmed Clinical LaboratoriesIstanbulTurkey
  4. 4.Clinic of CardiologyDr Siyami Ersek Thoracic and Cardiovascular Surgery Center Training and Research HospitalIstanbulTurkey

Personalised recommendations