Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study

Authors

  • Naguib Zohir Cairo University, Clinical and Chemical Pathology, 542 ElKhazan street, Cairo 24434
  • Reham Afifi Cairo University, Clinical and Chemical Pathology, 542 ElKhazan street, Cairo 24434
  • Asmaa Ahmed Cairo University, Clinical and Chemical Pathology, 542 ElKhazan street, Cairo 24434
  • Zinab Aly Cairo University, Clinical and Chemical Pathology, 542 ElKhazan street, Cairo 24434
  • Mehry Elsobekey Opthalmology Institute, Opthalmology, Cairo
  • Heba Kareem Cairo University, Internal Medicine, Cairo
  • Rehab Helmy Cairo University, Clinical and Chemical Pathology, 542 ElKhazan street, Cairo 24434

DOI:

https://doi.org/10.3889/oamjms.2013.015

Keywords:

Warfarin, VKORC1, Calumenin, CYP2C9, Gene, polymorphism.

Abstract

Background: Oral anticoagulant therapy is conditioned by environmental and genetic factors.

Objectives: To verify the effect of the calumenin, cytochrome P-450 variants and VKORC1 genetic polymorphisms on the response to warfarin therapy and warfarin dose adjustment.

Patients and Methods: We selected fifty warfarin treated patients with dose adjusted at INR value between 2 and 3. PCR-RFLP is used for of calumenin gene polymorphism. Insitu Hybridization was used for identification of VKORC1 promoter and CYP2C9 variants polymorphisms.

Results: The warfarin dose in the patients with Calumenin and CYP2C9 genetic polymorphism was lower than the wild type gene. The warfarin dose in the patients with VKORC1 variants was statistically lower compared to that of the wild-type. The presence of combined CYP2C9 genetic variants and VKORC1 polymorphism was associated with lower warfarin dose than that the wild types.

Conclusion: Calumenin (CALU) might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy.

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References

Wallin R, Hutson SM, Cain D, Sweatt A, Sane DC. A molecular mechanism for genetic warfarin resistance in the rat. Faseb J. 2001; 15:2542–2544.

Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008; 359(9):938-949.

Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem. 1985;54:459-77.

Cain D, Hutson SM, Wallin R. J Biol Chem.1998; 273, 4982–4989

Smith P, Arnesen H, HolmeI. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engi J Med. 1990; 323:147-152

Berkner KL. The vitamin K dependent carboxylase. J Nutr 2000, 130:1877-80.

Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics. 2003; 13:247–252.

Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J. 2004; 4:40–48.

Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadée W. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood. 2008; 112(4):1013-1021.

Strubbins M, Harries L, Smith G, Tarbit M, Wolf C. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics. 1996; 6:429.

Schwarz UI. Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest. 2003; 33(Suppl 2): 23–30.

Aithal G, Day C, Kesteven P, Daly A. Association of polymorphisms in the cytochrtomeP450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999; 353:717.

Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P 450 2C9 genotype. Thromb Haemost. 2005; 93(4): 700-705.

Wajih N, Sane DC, Hutson SM, Wallin R The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. J Biol Chem. 2004; 279:25276–25283.

Kollers S. Confirmation of the mapping of the porcine Calumenin gene (CALU) to chromosome 18. Anim Genet. 2005; 36: 177-178.

Vecsler M, Loebstein R, Almog S, Kurnit D, Goldman B, Halkin H, Gak E. Combined genetic profiles of components and regulators of the vitamin k-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost. 2006; 95:205-211.

Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006; 166(2):241–6.

Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008; 358:999-1008.

Millican EA, Lenzini PA, Milligan PE, et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood. 2007; 110:1511-1515.

FDA approves updated warfarin (Coumadin) prescribing information. Press release of the Food and Drug Administration, Rockville, MD, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed May 19, 2008.

Nan S, Wen T, Deyin X, Dongxin L. CYP1A1 polymorphism and risk of lung cancer in relation to tobacco smoking, the case control study in China’’ Departement of etiology, Carcinogenesis, Cancer institute, Chinese academy of medical science, Peking union medical college, Peijing 100021, China. 2001; 22(1):11- 16.

González-Conejero R., Corral J., Roldán V., Ferrer F., Sánchez-Serrano I., Sánchez-Blanco J.J., Marín F. and Vicente V. The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol. J Thromb Haemosta. 2007; 5: 1701-1706.

Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J. 2007; 7: 99-111.

Hermida J, Zarza J, Alberca I, Montes R, López ML, Molina E, Rocha E. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood. 2002 99: 4237-4239.

Taube J , Halsal D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood. 2000; 96: 1816-1819.

Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P, Daly AK, Wynne H. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clinical Pharmacology & Therapeutics. 2004; 75, 204–212.

Ozer N, Cam N, Tangurek B, Ozer S, Uyarel H, Oz D, Guney MR and CiloGln F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population. Heart Vessels. 2010; 25(2):155-62.

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; 106:2329-2333.

Miao L, Yang J, Huang C and Shen Z. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol. 2007; 63(12):1135-41.

Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, Clarke JL, James BC and Anderson JL. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis. 2006; 22(3):191-7.

Yuan HY, Chen JJ, Lee MT, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005; 14:1745-1751.

Lee SC, Ng SS, Oldenburg J, et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population. Clin Pharmacol Ther. 2006; 79:197-205.

Kimura R, Miyashita K, Kokubo Y, et al. Genotypes of vitamin K epoxide reductase, gammaGlntamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res. 2007; 120:181-186.

Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D, Gaston L, Waddell CD, Chirico MJ and Johnson JA. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther. 2006; 79(4):291-302.

Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, Siva A, Saip S, Johnson JA. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol. 2008; 64(9):889-94.

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Published

2013-12-15

How to Cite

1.
Zohir N, Afifi R, Ahmed A, Aly Z, Elsobekey M, Kareem H, Helmy R. Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study. Open Access Maced J Med Sci [Internet]. 2013 Dec. 15 [cited 2021 Apr. 12];1(1):76-82. Available from: https://oamjms.eu/index.php/mjms/article/view/oamjms.2013.015

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Section

B - Clinical Sciences