Abstract
Warfarin is an anticoagulant prescribed in the treatment and prevention of thrombosis. Variation in dose requirements is different for everyone, and genetic factors have an effect on dose variation. Polymorphism of vitamin K epoxide reductase complex 1 (VKORC1) gene is identified as the main genetic factor involved in warfarin dosage requirement variations. This study aims to determine the frequency of VKORC1 polymorphism in patients using warfarin from Kerman city and investigated association between VKORC1 gene polymorphism and patient characteristics with warfarin dose requirement. A total of 112 patients taking warfarin with stable dose requirements enrolled in the study. DNA samples from these patients were genotyped for VKORC1 gene polymorphism by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP) and examined associations between demographic characteristics (e.g. age, sex, smoking, etc.) and genetic factors with maintenance dose of warfarin. The most common genotype was VKORC1 GA (48.2%). genotype frequency subjects carried VKORC1 GG and AA were 39.3% and 12.5%, respectively. In addition, a significant relationship was found between VKORC1-1639G>A and the daily dose of warfarin (P = 0.011, R2 = 0.080). The frequencies of the VKORC1-1639 A alleles were significantly lower than VKORC1-1639 G alleles and required fewer warfarin dose.
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Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol. 2001;114:271–80.
Piatkov I, Rochester C, Jones T, Boyages S. Warfarin toxicity and individual variability-clinical case. Toxins. 2010;2:2584–92. https://doi.org/10.3390/toxins2112584.
Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 2012;8:563–76. https://doi.org/10.2217/fca.12.31.
Mazzaccara C, Conti V, Liguori R, Simeon V, Toriello M, Severini A, et al. Warfarin anticoagulant therapy: a Southern Italy pharmacogenetics-based dosing model. PLoS One. 2013;8:e71505. https://doi.org/10.1371/journal.pone.0071505.
Mahajan P, Meyer KS, Wall GC, Price HJ. Clinical applications of pharmacogenomics guided warfarin dosing. Int J Clin Pharm. 2011;33:10–9. https://doi.org/10.1007/s11096-011-9486-1.
Burmester JK, Berg RL, Glurich I, Yale SH, Schmelzer JR, Caldwell MD. Absence of novel CYP4F2 and VKORC1 coding region DNA variants in patients requiring high warfarin doses. Clin Med Res. 2011;9:119–24. https://doi.org/10.3121/cmr.2011.951.
You JH. Pharmacoeconomic evaluation of warfarin pharmacogenomics. Expert Opin Pharmacother. 2011;12:435–41. https://doi.org/10.1517/14656566.2011.521153.
Wu AH. Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteom. 2011;8:12. https://doi.org/10.1186/1559-0275-8-12.
Lane S, Al-Zubiedi S, Hatch E, Matthews I, Jorgensen AL, Deloukas P, et al. The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. Br J Clin Pharmacol. 2012;73:66–76. https://doi.org/10.1111/j.1365-2125.2011.04051.x.
Pavani A, Naushad SM, Rupasree Y, Kumar TR, Malempati AR, Pinjala RK, et al. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenom J. 2012;12:306–11. https://doi.org/10.1038/tpj.2011.4.
Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427:541–4. https://doi.org/10.1038/nature02254.
Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med. 2001;134:409–17.
Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8s–21s.
Kamali F, Wynne H. Pharmacogenetics of warfarin. Annu Rev Med. 2010;61:63–75. https://doi.org/10.1146/annurev.med.070808.170037.
Kabalak PA, Savas I, Akar N, Demir N, Egin Y. Frequency of vitamin K oxidoreductase complex subunit-1 (VKORC1) polymorphisms and warfarin dose management in patients with venous thromboembolism. Pharmacogenom J. 2018;18:646–51. https://doi.org/10.1038/s41397-018-0037-1.
Poopak B, Rabieipoor S, Safari N, Naraghi E, Sheikhsofla F, Khosravipoor G. Identification of CYP2C9 and VKORC1 polymorphisms in Iranian patients who are under warfarin therapy. Int J Hematol Oncol Stem Cell Res. 2015;9:185–92.
Alzahrani AM, Ragia G, Hanieh H, Manolopoulos VG. Genotyping of CYP2C9 and VKORC1 in the Arabic population of Al-Ahsa, Saudi Arabia. Biomed Res Int. 2013;2013:315980. https://doi.org/10.1155/2013/315980.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
Shehab N, Sperling LS, Kegler SR, Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170:1926–33. https://doi.org/10.1001/archinternmed.2010.407.
Ni X, Zhang W, Huang RS. Pharmacogenomics discovery and implementation in genome-wide association studies era. Wiley Interdiscip Rev Syst Biol Med. 2013;5:1–9. https://doi.org/10.1002/wsbm.1199.
DARILMAZ YÜCE G. Effect of genetic variations on adjusting of warfarin dose. Tuberculosis Thorax. 2014;62:236–42.
Wen MS, Lee M, Chen JJ, Chuang HP, Lu LS, Chen CH, et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther. 2008;84:83–9. https://doi.org/10.1038/sj.clpt.6100453.
Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, 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;106:2329–33. https://doi.org/10.1182/blood-2005-03-1108.
Greaves M. Pharmacogenetics in the management of coumarin anticoagulant therapy: the way forward or an expensive diversion? PLoS Med. 2005;2:e342. https://doi.org/10.1371/journal.pmed.0020342.
Borgiani P, Ciccacci C, Forte V, Sirianni E, Novelli L, Bramanti P, et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. 2009;10:261–6. https://doi.org/10.2217/14622416.10.2.261.
Zambon CF, Pengo V, Padrini R, Basso D, Schiavon S, Fogar P, et al. VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study. Pharmacogenomics. 2011;12:15–25. https://doi.org/10.2217/pgs.10.162.
D'Andrea G, D'Ambrosio RL, Perna PD, Chetta M, Santacroce R, Brancaccio V, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105:645–9. https://doi.org/10.1182/blood-2004-06-2111.
Cini M, LEGNANI C, COSMI B, GUAZZALOCA G, VALDRE L, FRASCARO M, et al. A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms. Eur J Clin Pharmacol. 2012;68:1167–74. https://doi.org/10.1007/s00228-012-1226-5.
Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics. 2010;11:781–91. https://doi.org/10.2217/pgs.10.49.
Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis. Thrombosis Res. 2010;125:e159–166. https://doi.org/10.1016/j.thromres.2009.10.017.
Limdi NA, Arnett DK, Goldstein JA, Beasley TM, McGwin G, Adler BK, et al. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenomics. 2008;9:511–26. https://doi.org/10.2217/14622416.9.5.511.
Miura T, Nishinaka T, Terada T, Yonezawa K. Relationship between aging and dosage of warfarin: the current status of warfarin anticoagulant therapy for Japanese outpatients in a department of cardiovascular medicine. J Cardiol. 2009;53:355–60. https://doi.org/10.1016/j.jjcc.2008.12.003.
Khoury G, Sheikh-Taha M. Effect of age and sex on warfarin dosing. Clin Pharmacol. 2014;6:103–6. https://doi.org/10.2147/cpaa.s66776.
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The authors appreciate Dr Dabiri, Member of Pathology Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, for his help.
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Soltani Banavandi, M.J., Satarzadeh, N. Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province. Pharmacogenomics J 20, 574–578 (2020). https://doi.org/10.1038/s41397-019-0146-5
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DOI: https://doi.org/10.1038/s41397-019-0146-5
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