To study the distribution of alleles and genotypes of polymorphic markers of genes CYP2C9 and VKORC1 of Russian patients who live in Moscow, and in order to assess the influence of genetic factors on warfarin therapy 400 patients have been genotyped. The dosage of warfarin which is required for achievement of INR target values has been different among owners of different geno- types of polymorphic markers of genes CYP2C9 . Meanwhile the highest average dose has been required for genotype *1/*1 and the lowest – for owners of alleles *2 and *3 . For polymorphism G(- 1639)A of the gene VKORC1 the dosage of warfarin which is required for achievement of the INR target values, has been different among owners of different genotypes. The highest average dose has been required for genotype GG, and the lowest – for genotype AA. The results will allow to work out more accurate algorithm of choosing of the initial dose of warfarin depending on the genotypes of polymorphic markers of genes CYP2C9 and VKORC1.

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  1. Prendergast F G, Mann K G. Differentiation of metal ion-induced transitions of prothrombin fragment J. Biol. Chem. 1977; 252 (3): 840-50.
  2. Borowski M, Furie B C, Bauminger S, Furie B. Prothrombin requires two sequential metal-dependent conformational transitions to bind phospholipid. Conformation-specific antibodies directed against the phospholipid-binding site on prothrombin. J. Biol. Chem. 1986; 261 (32): 14969-75.
  3. Nelsestuen G L. Role of gamma-carboxyglutamic acid. An unusual protein transition required for the calcium-dependent binding of prothrombin to phospholipid. J. Biol. Chem. 1976; 251 (18): 5648-56.
  4. Nelsestuen G L, Zytkovicz T H, Howard J B. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. J. Biol. Chem. 1974; 249 (19): 6347-50.
  5. Choonara I A, Malia R G, Haynes B P 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): 1-7.
  6. Owen Ryan P., Gong Li, Sagreiya Hersh, Klein Teri E., Altman Russ B. VKORC1 Pharmaco-genomics Summary. Pharmacogenet Genomics. 2010; 20 (10): 642-44.
  7. Wadelius M, Pirmohamed M. Pharmaco-genetics of warfarin: current status and future challenges. Pharmacogenomics J. 2007; 7 (2): 99-111.
  8. Schwarz U I. Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest. 2003; 33 Suppl 2: 23-30.
  9. Tai Guoying, Farin Frederico, Rieder Mark J et al. In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose. Pharmacogenet Genomics. 2005; 15 (7): 475-81.
  10. Muszkat Mordechai, Blotnik Simcha, Elami Amir, Krasilnikov Irena, Caraco Yoseph. Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions. Clin Ther. 2007; 29 (3): 427-37.
  11. Higashi Mitchell K, Veenstra David L, Kondo L Midori et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002; 287 (13): 1690-98.
  12. Li Tao, Chang Chun-Yun, Jin Da-Yun et al. Identification of the gene for vitamin K epoxide reductase. Nature. 2004; 427 (6974): 541-44.
  13. Rost Simone, Fregin Andreas, Ivaskevicius Vytautas et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004; 427 (6974), 537-41.
  14. Obayashi Kyoko, Nakamura Katsunori, Kawana Junichi et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther. 2006; 80 (2): 169-78.
  15. Loebstein Ronen, Dvoskin Ilana, Halkin Hillel et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood. 2007;109 (6): 2477-80.
  16. D'Andrea Giovanna, D'Ambrosio Rosa Lucia, Di Perna Pasquale et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005; 105 (2): 645-49.
  17. Rieder Mark J, Reiner Alexander P, Gage Brian F et al. Effect of VKORC1 haplotypes on transcriptional. regulation and warfarin dose. N Engl J Med. 2005; 352 (22): 2285-93.
  18. Harrington Dominic J, Underwood Sarah, Morse Colin et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost. 2005; 93 (1): 23-26.
  19. Bodin L, Horellou M H, Flaujac C, Loriot M A, Samama M M. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost. 2005;3 (7): 1533-35.
  20. Yuan Hsiang-Yu, Chen Jin-Jer, Lee M T Michael et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and interethnic differences in warfarin sensitivity. Hum Mol Genet. 2005;14 (13): 1745-51.
  21. Geisen Christof, Watzka Matthias, Sittinger Katja et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. 2005; 94 (4): 773-9.
  22. Aquilante Christina L., Langaee Taimour Y., Lopez Larry M. et al. 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.
  23. Takahashi Harumi, Wilkinson Grant R, Nutescu Edith A 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): 101-110.
  24. Hynicka Lauren M, Cahoon William D Jr, Bukaveckas Bonny L. Genetic testing for warfarin therapy initiation. Ann Pharmacother. 2008; 42 (9): 1298-1303.
  25. Johns M B, Paulus-Thomas J E. Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal Biochem. 1989;180 (2): 276-8.
  26. Калькулятор для расчета статистики в исследованиях «случай-контроль» [ calculator_or.php].
  27. Lindh Jonatan D, Lundgren Stefan, Holm Lennart, Alfredsson Lars, Rane Anders. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther. 2005; 78 (5): 540-50.
  28. Peyvandi Flora, Spreafico Marta, Siboni Simona Maria, Moia Marco, Mannucci Pier Mannuccio. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy. Clin Pharmacol Ther. 2004; 75 (3): 198-203.
  29. Joffe Hylton V, Xu Ruliang, Johnson F Bradley et al. Warfarin dosing and cytochrome P450 2C9 poly- morphisms. Thromb Haemost. 2004; 91(6): 1123-28.
  30. Leung A Y, Chow H C, Kwong Y L et al. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood. 2001;98 (8): 2584-87.
  31. Tabrizi Arash Rafii, Zehnbauer Barbara A, Borecki Ingrid B et al. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg. 2002; 194 (3): 267-73.
  32. Scordo Maria Gabriella, Pengo Vittorio, Spina Edoardo et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther. 2002; 72 (6): 702-10.
  33. Visser Loes E, van Vliet Martin, van Schaik Ron H N et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics. 2004; 14 (1): 27-33.
  34. Voora Deepak, Eby Charles, Linder Mark W et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005; 93 (4):700-705.
  35. Taube J, Halsall 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 (5): 1816-19.



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Copyright (c) 2013 Zotova I.V., Nikitin A.G., Fattakhova E.N., Brovkin A.N., Khodyrev D.S., Lavrikova E.Y., Isaeva M.Y., Kosukhina A.S., Nosikov V.V., Zateyshchikov D.A.

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