Volume 6, Issue 2 (7-2024)
pbp 2024, 6(2): 15-24 |
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Baharvand Ahmadi B, Nafari A, Ahmadi K, Heydari Nazarabad V, Mohammadi R, Almasian M et al . Investigation of the Effects of Genetic Variations in CYP2C9 and VKORC1 on Warfarin Dose Requirements Among Iranian Patients from Khorramabad, Lorestan Province, West of Iran. pbp 2024; 6 (2) :15-24
URL: http://pbp.medilam.ac.ir/article-1-248-en.html
URL: http://pbp.medilam.ac.ir/article-1-248-en.html
Babak Baharvand Ahmadi1 
, Amirhossein Nafari2 , Kolsoum Ahmadi3 , Vahide Heydari Nazarabad3 , Rasool Mohammadi4 , Mohammad Almasian5 , Ali Asghar Kiani * 6
, Amirhossein Nafari2 , Kolsoum Ahmadi3 , Vahide Heydari Nazarabad3 , Rasool Mohammadi4 , Mohammad Almasian5 , Ali Asghar Kiani * 6
1- 1. Department of Cardiology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
2- 2. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
3- 3. Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
4- 4. Department of Epidemiology and Biostatistics, School of Public Health and Nutrition, Lorestan University of Medical Sciences, Khorramabad, Iran
5- 5. School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
6- 6. Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Lorestan University of Medical Sciences, Khorramabad, Iran ,kiani.a@lums.ac.ir
2- 2. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
3- 3. Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
4- 4. Department of Epidemiology and Biostatistics, School of Public Health and Nutrition, Lorestan University of Medical Sciences, Khorramabad, Iran
5- 5. School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
6- 6. Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Lorestan University of Medical Sciences, Khorramabad, Iran ,
Abstract: (312 Views)
Background: Warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index, poses challenges in determining the appropriate dosage due to genetic variations among individuals. Incorrect dosing of warfarin can lead to catastrophic adverse events. Observational studies have shown that single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes significantly influence warfarin dose requirements. This study aimed to examine the impact of various genotypes on warfarin dose requirements among Iranian patients.
Methods: Blood samples were collected from 117 patients and stored in tubes containing EDTA. DNA was extracted, and the different alleles and genotypes of the studied SNPs were identified using the PCR-RFLP technique.
Results: Among the 117 patients, no significant differences were observed in the mean daily warfarin dose requirement among the genotypes of the CYP2C93 (1075A>C) polymorphism. However, significant differences were found among the genotypes of CYP2C92 (430C>T). Furthermore, the mean daily warfarin dose requirements varied significantly among the wild-type, heterozygous, and mutant genotypes for two VKORC1 polymorphisms: VKORC1 (1173C>T) and VKORC1 (1639G>A).
Conclusion: Our findings demonstrate that CYP2C9 and VKORC1 polymorphisms significantly affect warfarin maintenance dose requirements in Iranian patients. This information can improve the prediction of appropriate warfarin dosages and reduce the risk of over-anticoagulation or under-anticoagulation.
Received: 2024/03/25 | Accepted: 2024/09/4 | Published: 2024/07/31
References
1. Penttilä T, Lehto M, Niiranen J, et al. Differences in the risk of stroke, bleeding, and mortality between female and male patients with atrial fibrillation during warfarin therapy. J Am Coll Cardiol. 2018;71(11). doi: 10.1016/S0735-1097(18)30862-7.
2. Shah RR. Genotype‐guided warfarin therapy: Still of only questionable value two decades on. J Clin Pharm Ther. 2020;45(3):547-60. doi: 10.1111/jcpt.13089.
3. Zhang J, Chen Z, Chen C. Impact of CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis. Meta Gene. 2016;9:197-209. doi: 10.1016/j.mgene.2016.06.005.
4. Tang W, Shi QP, Ding F, et al. Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: A novel systematic review and meta-analysis of 53 studies. Int J Clin Pharmacol Ther. 2017;55(4):304-19. doi: 10.5414/CP203087.
5. Lewis BC, Nair PC, Heran SS, et al. Warfarin resistance associated with genetic polymorphism of VKORC1: Linking clinical response to molecular mechanism using computational modeling. Pharmacogenet Genomics. 2016;26(1):44-50. doi: 10.1097/FPC.0000000000000183.
6. Cavalli M, Pan G, Nord H, et al. Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose. Pharmacogenomics. 2016;17(12):1305-14. doi: 10.2217/pgs-2016-0104.
7. Al-Jaibeji HS, John A, Al-Gazali L, et al. Allele and genotype frequencies of the two single nucleotide polymorphisms in the VKORC1 gene that are most important for warfarin treatment among Emiratis. Hamdan Med J. 2016;212(3849):1-10. doi: 10.7707/hmj.v212.3849.
8. Vandell AG, Walker J, Brown KS, et al. Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism. Heart. 2017;103:1853-1860. doi: 10.1136/heartjnl-2016-310051.
9. Takahashi H, Wilkinson GR, Nutescu EA, et al. 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. 2006;16(2):101-10. doi: 10.1097/01.fpc.0000184957.29220.8b.
10. Maddison J, Somogyi AA, Jensen BP, et al. The pharmacokinetics and pharmacodynamics of single-dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype. Br J Clin Pharmacol. 2013;75(1):208-16. doi: 10.1111/j.1365-2125.2012.04222.x.
11. Kosaki K, Yamaghishi C, Sato R, et al. 1173C> T polymorphism in VKORC1 modulates the required warfarin dose. Pediatr Cardiol. 2006;27(6):685-8. doi: 10.1007/s00246-006-1323-1.
12. Khaleqsefat E, Khalaj-Kondori M, Jabbarpour B, Battaloğlu E. Warfarin maintenance dose associated with genetic polymorphisms of CYP2C9. Hippokratia. 2017;21(2):93-6. Link.
13. Abohelaika S, Wynne H, Avery P, et al. Effect of genetic and patient factors on warfarin pharmacodynamics following warfarin withdrawal: Implications for patients undergoing surgery. Thromb Res. 2018;171:167-70. doi: 10.1016/j.thromres.2018.09.005.
14. Visser LE, van Schaik RH, van Vliet M, et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C92 or CYP2C93 alleles on acenocoumarol or phenprocoumon. Thromb Haemost. 2004;91(01):61-6. doi: 10.1160/TH03-06-0363.
15. Zhang J, Tian L, Huang J, et al. Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: A systematic review and meta‐analysis. Cardiovasc Ther. 2017;35(1):26-32. doi: 10.1111/1755-5922.12230.
16. Agrawal S, Heiss MS, Fenter RB, et al. Impact of CYP2C9‐Interacting Drugs on Warfarin Pharmacogenomics. Clin Transl Sci. 2020;13(5):941-9. doi: 10.1111/cts.12775.
17. Topkara VK, Knotts RJ, Jennings DL, et al. Effect of CYP2C9 and VKORC1 gene variants on warfarin response in patients with continuous-flow left ventricular assist devices. ASAIO J. 2016;62(5):558-64. doi: 10.1097/MAT.0000000000000380.
18. Natarajan S, Ponde CK, Rajani RM, et al. Effect of CYP2C9 and VKORC1 genetic variations on warfarin dose requirements in Indian patients. Pharmacol Rep. 2013;65(5):1375-82. doi: 10.1016/S1734-1140(13)71407-8.
19. Ahmadi K, Soleimani A, Irani S, et al. DNMT3B−579 G>T Promoter Polymorphism and the Risk of Gastric Cancer in the West of Iran. J Gastrointest Cancer. 2018;49(2):167-71. doi: 10.1007/s12029-017-9970-5.
20. Saffian SM, Duffull SB, Wright DF. Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring≥7 mg Daily: A Systematic Review and Meta‐analysis. Clin Pharmacol Ther. 2017;102(2):297-304. doi: 10.1002/cpt.602.
21. Kim IS, Kim HJ, Kim TH, et al. Non-vitamin K antagonist oral anticoagulants have better efficacy and equivalent safety compared to warfarin in elderly patients with atrial fibrillation: a systematic review and meta-analysis. J Cardiol. 2018;72(2):105-12. doi: 10.1016/j.jjcc.2018.02.015.
22. Mili FD, Allen T, Wadell PW, et al. VKORC1-1639A allele influences warfarin maintenance dosage among Blacks receiving warfarin anticoagulation: a retrospective cohort study. Future Cardiol. 2018;14(1):15-26. doi: 10.2217/fca-2017-0030.
23. Huang TS, Zhang L, He Q, et al. DNA sensors to assess the effect of VKORC1 and CYP2C9 gene polymorphisms on warfarin dose requirement in Chinese patients with atrial fibrillation. Australas Phys Eng Sci Med. 2017;40(1):249-58. doi: 10.1007/s13246-017-0527-y.
24. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 2009;5(3). doi: 10.1371/journal.pgen.1000433.
25. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329-33. doi: 10.1182/blood-2005-03-1036.
26. Flora DR, Rettie AE, Brundage RC, Tracy TS. CYP2C9 genotype-dependent warfarin pharmacokinetics: Impact of CYP2C9 genotype on R- and S-warfarin and their oxidative metabolites. J Clin Pharmacol. 2017;57(3):382-93. doi: 10.1002/jcph.836.
27. Ozgon GO, 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(9):889-94. doi: 10.1007/s00228-008-0488-8.
28. Yuan HY, Chen JJ, Lee MM, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005;14(13):1745-51. doi: 10.1093/hmg/ddi180.
29. Hosseinkhani Z, Sadeghalvad M, Norooznezhad F, et al. The effect of CYP2C92, CYP2C93, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah. Res Pharm Sci. 2018;13(4):377-84. doi: 10.4103/1735-5362.235961.
30. Azarpira N, Namazi S, Hendijani F, et al. Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep. 2010;62(4):740-6. doi: 10.1016/S1734-1140(10)70341-1.
31. Banavandi MJ, Satarzadeh N. Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province. Pharmacogenomics J. 2020;20(4):574-8. doi: 10.1038/s41397-019-0116-0.
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