Emin Murat AKBAŞ, Fuat ERDEM, Mehmet GÜNDOĞDU, İlhami KİKİ, Hülya AKSOY, Serkan CERRAH, Rahşan YILDIRIM, Abdulkadir YILDIRIM, Fatih KURNAZ

CYP2C9 gene polymorphisms and warfarin dose requirement: a single-center experience in Turkey

In this study, we aimed to evaluate the relationship between genetic structure and daily dose requirement in patients under warfarin therapy presenting at our hospital. Materials and methods: A total of 80 patients (45 female and 35 male) aged between 29 and 80 years (mean age: 59.86 ± 14.46 years), using warfarin for at least 1 month and presenting at Atatürk University Medical Faculty Outpatient Clinic between May 2009 and May 2010, were included in the study. Analysis of CYP2C9 1075 A>C and CYP2C9 430 C>T polymorphisms were performed using polymerase chain reaction (PCR) and the reverse-hybridization method. Results: Patients with CYP2C9 genotype variants *2/*2, *2/*3, and *3/*3 required 3.40 mg/day, which was 1.57 mg less warfarin per day than patients with the wild-type genotype (*1/*1) (4.97 mg/day), and this difference was statistically significant (P = 0.014). Additionally, the patients with *1/*2 and *1/*3 genotypes required 3.93 mg/day, which was 1.04 mg less warfarin per day than those with the wild-type genotype (P = 0.01). Conclusion: Because patients with *2 and *3 variants of the CYP2C9 gene are at a high risk for bleeding while taking an oral anticoagulant, clinicians should start at lower doses of warfarin in these patients and should make strict dose adjustments.

Anahtar Kelimeler:

Key words: CYP2C9 1075 A>C, CYP2C9 430 C>T, warfarin, polymorphism

CYP2C9 gene polymorphisms and warfarin dose requirement: a single-center experience in Turkey

Keywords:

Key words: CYP2C9 1075 A>C, CYP2C9 430 C>T, warfarin, polymorphism,

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Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D et al. Risk factors for complications of chronic anticoagulation: a multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: 511-20.
Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315-28. 3. Çebi N, Tanrıverdi S. Aetiology of deep vein thrombosis in 63 Turkish patients. Turk J Med Sci 2009; 39: 223-27.
Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003; 41: 1633-52. 5. Chua YA, Abdullah WZ, Gan SH. Development of a high- performance liquid chromatography method for warfarin detection in human plasma. Turk J Med Sci 2012; 42: 930-41. 6. Ceylan BÇ, Yavuz L, Eroğlu F, Gülmen Ş, Tarhan ÖR, Alaca A. Th e eff ects of adjuvant therapies for sepsis on hepatic and renal function: a retrospective analysis of 108 ICU patients. Turk J Med Sci 2010; 40: 949-57.
Sayitoğlu MA, Yıldız İ, Hatırnaz Ö, Özbek U. Common Cytochrome p4503A (CYP3A4 and CYP3A5) and Th iopurine S-Methyl Transferase (TPMT) Polymorphisms In Turkish Population. Turk J Med Sci 2006; 36: 11-15. 8. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T et al. Hydroxylation of warfarin by human cDNA- expressed cytochrome P450: a role for P4502C9 in the etiology of (S)-warfarin drug interactions. Chem Res Toxicol 1992; 5: 54-9.
Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6: 429-39.
Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired S-warfarin metabolism catalyzed by R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39-42.
Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 7: 361-7.
Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P4502C9: baculovirus- mediated expression, purifi cation, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild- type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447-58.
Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ et al. Genetic polymorphism of CYP2C9 and its eff ect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995; 5: 389-92.
Takahashi H, Kashima T, Nomizo Y, Muramoto N, Shimizu T, Nasu K et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having diff erent CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Th er 1998; 63: 519-28.
Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-8.
Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Infl uence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Th er 2002; 72: 702-10.
Wilke RA, Berg RL, Vidaillet HJ, Caldwell MD, Burmester JK, Hillman MA. Impact of age, CYP2C9 genotype and concomitant medication on the rate of rise for prothrombin time during the fi rst 30 days of warfarin therapy. Clin Med Res 2005; 3: 207-13.
Taube J, Halsall D, Baglin T. Infl uence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816-9.
Caldwell MD, Berg RL, Zhang KQ, Glurich I, Schmelzer JR, Yale SH et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007; 5: 8-16.
White PJ. Patient factors that infl uence warfarin dose response. J Pharm Pract 2010; 23: 194-204.
Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108-21.
Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Med Ann Intern 2000; 133: 687-95.
McMahan DA, Smith DM, Carey MA, Zhou XH. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med 1998; 13: 311-6.
Veenstra DL, Blough DK, Higashi MK, Farin FM, Srinouanprachan S, Rieder MJ et al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Th er 2005; 77: 353-64.
Atrial Fibrillation Investigators.Risk factors for stroke and effi cacy of antithrombotic therapy in atrial fi brillation. Analysis of pooled data from fi ve randomized controlled trials. Arch Intern Med 1994; 154: 1449-57.
Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108-21.
Ngow HA, Wan Khairina WM, Teh LK, Lee WL, Harun R, Ismail R et al. CYP2C9 polymorphism: prevalence in healthy and warfarin-treated Malay and Chinese in Malaysia. Singapore Med J 2009; 50: 490-3.
uan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ et al. A novel functional VKORC1 promoter polymorphism is associated with interindividual and interethnic diff erences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-51.
Ozer N, Cam N, Tangurek B, Ozer S, Uyarel H, Oz D et al. Th e impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population. Heart Vessels 2010; 25: 155-62.
Yıldırım H, Tamer L, Sucu N, Atik U. Th e role of CYP2C9 gene polymorphisms on anticoagulant therapy aft er heart valve replacement. Med Princ Pract. 2008; 17:464-7.
Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol. 2008; 64: 889-94.
Yilmaz N, Erbağcı AB, Aynacioğlu AŞ. Cytochrome P4502C9 genotype in Southeast Anatolia and possible relation with some serum tumour markers and cytokines. Acta Biochim Pol 2001; 48: 775-82.