Investigation of CYP2C9 gene polymorphism in patients receiving warfarin therapy

Abstract

Purpose: The aim of the study is to investigate the relationship between CYP2C9 gene polymorphism status and weekly dose requirement and INR levels in patients who are receiving warfarin treatment and admitted to our hospital. Materials and Methods: A total of 100 patients and 100 control groups who applied to the Emergency Department of Pamukkale University Medical Faculty, who used warfarin treatment were included in the study. Results: CYP2C9*1 allele frequency 148 (74%), CYP2C9*2 allele frequency 17 (8.5%), CYP2C9*3 allele frequency 35 (17.5%), CYP2C9*1/1 genotype frequency 54 (%54), CYP2C9*1/2 genotype frequency 11 (11%), CYP2C9*1/3 genotype frequency 29 (29%), CYP2C9*2/3 genotype frequency 6 (6%) were found in the group using warfarin. When the warfarin group was measured according to CYP2C9 genotypes and alleles, there was no statistically significant difference between the genotypes or alleles in terms of INR levels (p=0.475 and p=0.483, respectively). In the INR measurements performed in the first control after the use of warfarin, the INR level was found to be significantly lower in individuals with wild type genotype or allele compared to individuals with other genotypes and alleles (p=0.038 and p=0.032 respectively). The peak INR value measured during warfarin treatment was likewise lower in wild-type individuals than in individuals with other genotypes or alleles (p=0.0001 and p=0.008, respectively). Conclusion: The fact that the first and peak INR values of patients carrying the mutant allele or genotypes of the CYP2C9 gene were higher than the non-mutated group reveals the effect of these alleles on warfarin metabolism.

Keywords

• CYP2C9 gene polymorphism
• warfarin
• anticoagulation

Varfarin tedavisi alan hastalarda CYP2C9 gen polimorfizminin araştırılması

Öz

Amaç: Çalışmanın amacı warfarin tedavisi almakta olup hastanemize başvuran hastalarda, CYP2C9 gen polimorfizmi durumu ile haftalık doz ihtiyacı, INR düzeyleri arasında ilişkiyi incelemektir. Gereç ve Yöntem: Pamukkale Üniversitesi Tıp Fakültesi Acil Servisine başvuran, warfarin tedavisi kullanan, toplam 100 hasta ve 100 kontrol grubu çalışma kapsamına alındı. Bulgular: Warfarin kullanan grupta CYP2C9*1 allel frekansı 148(%74), CYP2C9*2 allel frekansı 17(%8,5), CYP2C9*3 allel frekansı 35(%17,5), CYP2C9*1/1 genotip frekansı 54 (%54), CYP2C9*1/2 genotip frekansı 11(%11), CYP2C9*1/3 genotip frekansı 29 (%29), CYP2C9*2/3 genotip frekansı 6(%6) olarak saptandı. Warfarin grubunun CYP2C9 genotiplerine ve allellere göre acil servis başvurusundaki INR düzeylerine bakıldığında genotipler veya alleller arasında INR düzeyi açısından istatistiksel anlamlı farklılık saptanmadı (Sırasıyla p=0,475 ve p=0,483). Warfarin kullanılmaya başlandıktan sonra ilk kontrolde yapılan INR ölçümlerinde wild tip genotipe veya allele sahip bireylerde INR düzeyi diğer genotip ve allellere sahip bireylere göre belirgin olarak daha düşük saptandı (Sırasıyla p=0,038 ve p=0,032). Warfarin tedavisi sırasında ölçülen pik INR değeri de aynı şekilde wild tip bireylerde diğer genotip veya allellere sahip bireylere göre daha düşük saptandı (Sırasıyla p=0,0001 ve p=0,008). Sonuç: CYP2C9 geninin mutant allel veya genotiplerini taşıyan hastaların ilk ve pik INR değerlerinin mutasyonsuz olan gruba göre yüksek saptanmış olması bu allellerin warfarin metabolizmasına etkisini ortaya koymaktadır.

Anahtar Kelimeler

• CYP2C9 gen polimorfizmi
• warfarin
• antikoagülasyon

Kaynakça

1. 1. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993;118:511-520. doi: 10.7326/0003-4819-118-7-199304010-00005.
2. 2. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315‐328. doi:10.1016/0002-9343(93)90285-w
3. 3. Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 1992;102:352S‐363S. doi:10.1378/chest.102.4_supplement.352s
4. 4. Van der Meer FJ, Rosendaal FR, Vanderbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993;153:1557-1562. doi:10.1001/archinte.153.13.1557
5. 5. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study. Lancet 1996;348:423-428. doi:10.1016/s0140-6736(96)01109-9
6. 6. Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association/American College of Cardiology Foundation. American Heart Association/ American College of Cardiology Foundation guide to warfarin therapy. J AmColl Cardiol 2003;41:1633-1652. doi:10.1016/s0735-1097(03)00416-9
7. 7. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. linical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000;160:3431‐3436. doi:10.1001/archinte.160.22.3431
8. 8. Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol 1988;25:1-7. doi: 10.1111/j.1365-2125.1988.tb03274.x.

9. 9. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992;5:54-59. doi: 10.1021/tx00025a009.
10. 10. Laura Dean. Warfarin Therapy and the Genotypes CYP2C9 and VKORC1. Created: March 8, 2012; Last Update: June 8, 2016. https://www.ncbi.nlm.nih.gov/books/n/gtrbook/warfarin/bin/20160608warfarin.pdf (Son erişim tarihi 15.05.2020).
11. 11. 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. doi:10.1097/00008571-199402000-00005
12. 12. Steward DJ, Haining RL, Henne KR, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997;7:361-367. doi: 10.1097/00008571-199710000-00004.
13. 13. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P4502C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996;333:447-458. doi:10.1006/abbi.1996.0414
14. 14. Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997;7:203-210. doi:10.1097/00008571-199706000-00005.
15. 15. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353:717-719. doi:10.1016/S0140-6736(98)04474-2
16. 16. Ogg MS, Brennan P, Meade T, Humphries SE. CYP2C9*3 allelic variant and bleeding complications. Lancet 1999;354:1124. doi:10.1016/S0140-6736(05)76918-X
17. 17. Margaglione M, Colaizzo D, D’Andrea G, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000;84:775-778. PMID: 11127854.
18. 18. Freeman BD, Zehnbauer BA, McGrath S, Borecki I, Buchman TG. Cytochrome P450 polymorphisms are associated with reduced warfarin dose. Surgery 2000;128:281-285. doi:10.1067/msy.2000.107283
19. 19. Furuya H, Fernandez-Salguero P, Gregory W, et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995;5:389‐392. doi:10.1097/00008571-199512000-00008
20. 20. Takahashi H, Kashima T, Nomizo Y, et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 1998;63:519‐528. doi:10.1016/S0009-9236(98)90103-5
21. 21. COUMADIN (warfarinsodium tablet) Princeton, NJ: Bristol-MyersSquibbPharmaCompany; 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d91934a0-902e-c26c-23ca-d5accc4151b6.(Son Erişim 14.11.2019)
22. 22. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002;72:702‐710. doi:10.1067/mcp.2002.129321
23. 23. Hillman MA, Wilke RA, Caldwell MD, Berg RL, Glurich I, Burmester JK. Relativeimpact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 2004;14:539–547. doi:10.1097/01.fpc.0000114760.08559.dc
24. 24. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J ClinPharmacol 2001;52:447–450. doi:10.1046/j.0306-5251.2001.01460.x
25. 25. Xiong Y, Wang M, Fang K, et al. A systematic genetic polymorphism analysis of the CYP2C9 gene in four different geographical Han populations in mainland China. Genomics 2011;97:277–281. doi:10.1016/j.ygeno.2010.11.004
26. 26. Dai DP, Xu RA, Hu LM, et al. CYP2C9 polymorphism analysis in Han Chinese populations: building the largest allele frequency database. Pharmacogenomics J 2014;14:85-92. doi:10.1038/tpj.2013.2
27. 27. Aynacioglu AS, Brockmöller J, Bauer S, et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J ClinPharmacol 1999;48:409-415. doi:10.1046/j.1365-2125.1999.00012.x
28. 28. Babaoglu MO, Yasar U, Sandberg M, et al. CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur J ClinPharmacol 2004;60:337-342. doi:10.1007/s00228-004-0785-5
29. 29. Dai DP, Xu RA, Hu LM, et al. CYP2C9 polymorphism analysis in Han Chinese populations: building the largest allelefrequency database. Pharmacogenomics J 2014;14:85-92. doi:10.1038/tpj.2013.2
30. 30. Xiong Y, Wang M, Fang K, et al. A systematic genetic polymorphism analysis of the CYP2C9 gene in four different geographical Han populations in mainland China. Genomics 2011;97:277-281. doi:10.1016/j.ygeno.2010.11.004
31. 31. Dagenais R, Wilby KJ, Elewa H, Ensom MHH. Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region. Drugs R D 2017;17:341-361. doi:10.1007/s40268-017-0195-7
32. 32. Dericioglu N, Babaoglu MO, Saygi S, Bozkurt A, Yasar U. Warfarin resistance with poor CYP2C9 activityand CYP2C9 *1*2 genotype. AnnPharmacother 2004;38:899. doi:10.1345/aph.1D450
33. 33. Siddiqi A, Khan DA, Khan FA, Naveed AK. Impact of CYP2C9 genetic polymorphism on warfarin dose requirements in Pakistani population. Pak J Pharm Sci 2010;23:417-422. PMID: 20884456.
34. 34. Blaisdell J, Jorge-Nebert LF, Coulter S, et al. Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 2004;14:527-537. doi:10.1097/01.fpc.0000114759.08559.51
35. 35. Anca D. Buzoianu, Adrian P Trifa, Dafin F Mureşanu, SorinCrişan, Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe Clin PharmacolTher 2002;72:702-710. doi:10.1111/j.1582-4934.2012.01606.x
36. 36. Oner Ozgon G, Langaee TY, Feng H, et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 2008;64:889-894. doi: 10.1007/s00228-008-0507-5.