Blood Reviews
Volume 22, Issue 3 , Pages 127-140 , May 2008

Oral anticoagulants: Pharmacogenetics: Relationship between genetic and non-genetic factors

  • Giovanna D’Andrea

      Affiliations

    • Genetica Medica, Dipartimento di Scienze Biomediche, Università di Foggia, Italy
    • ,
  • Rosa D’Ambrosio

      Affiliations

    • Genetica Medica, Dipartimento di Scienze Biomediche, Università di Foggia, Italy
    • ,
  • Maurizio Margaglione

      Affiliations

    • Genetica Medica, Dipartimento di Scienze Biomediche, Università di Foggia, Italy
    • Unita’ di Emostasi e Trombosi, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, Italy
    • Corresponding Author InformationCorresponding author.

References 

  1. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1998;114:445S
  2. Lake BJ. Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment food and chemical toxicology. Food Chem Toxicol. 1999;37:423–453
  3. De Vries JX, Schmitz-Kummer E. Development of a method for the analysis of warfarin and metabolites in plasma and urine. Am Clin Lab. 1995;14:20–21
  4. Cohen AJ. Critical review of the toxicology of coumarin with special reference to interspecies differences in metabolism and hepatotoxic response and their significance to man. Food and Cosmet Toxicol. 1979;17:277–289
  5. Fentem JH, Fry JR. Species differences in the metabolism and hepatotoxicity of coumarin. Comp Biochem Physiol. 1993;104:1–8
  6. Palareti G, Legnani C. Warfarin withdrawal. Pharmacokinetics-pharmacodynamics considerations. Clin Pharmacokinet. 1996;30:300–313
  7. Brekenridge AM. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol. 1978;15:19
  8. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979;4:1–15
  9. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, 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
  10. Kaminsky LS, Zhang Z. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73:67–74
  11. Ritschel WA, Hoffman KA, Tan HS, Sanders PR. Pharmacokinetics of coumarin upon i.v. administration in man. Drug Res. 1976;26:1382–1387
  12. Ritschel WA, Hoffman KA. Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form. J Clin Pharmacol. 1981;21:294–300
  13. Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med. 2003;3:221–230
  14. O Reilly RA. Warfarin metabolism and drug-drug interactions. In:  Wessler S,  Becker CG,  Nemerson Y editor. The new dimensions of warfarin prophylaxis. Advances in experimental medicine and biology. Vol.214:New York, NY: Plenum; 1986;p. 205–212
  15. O’ Reilly RA. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther. 1974;16:348–354
  16. Otagiri M, Maruyama T, Imai T, Suenga A, Imamura Y. A comparative study of the interaction of warfarin with human alpha 1- acid glycoprotein and human albumin. J Pharmacol. 1987;39:416–420
  17. Wang PP, Beaune P, Kaminsky LS, Dannan GA, Kadlubar FF, Lorrey D, et al. Purification and characterization of six cytochrome P-450 isozymes from human liver microsomes. Biochem. 1983;22:5375–5383
  18. Kaminsky LS, Dunbar DA, Wang PP, Beaune P, Lorrey D, Guengerich FP, et al. Human hepatic cytochrome P-450 composition as probed by in vitro microsomal metabolism of warfarin. Drug Metab Dispos. 1984;12:470–477
  19. Hermans JJ, Thijssen HH. The in vitro ketone reduction of warfarin and analogues. Substrate stereoselectivity, product stereoselectivity and species differences. Biochem Pharmacol. 1989;38:3365–3370
  20. Brian WR, Sari MA, Iwasaki M, Shimada T, Kaminsky LS, Guengerich FP. Catalytic activities of human liver cytochrome P-450 IIIA4 expressed in Saccharomyces cerevisiae. Biochem. 1990;29:11280–11292
  21. Kaminsky LS, de Morais SM, Faletto MB, Dunbar DA, Goldstein JA. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol. 1993;43:234–239
  22. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenet. 1996;6:1–42
  23. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126(Suppl 3):204S–233S
  24. Stafford DW. The vitamin K cycle. J Thromb Haemost. 2005;3:1873–1878
  25. Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. J Biol Chem. 1985;260:279–287
  26. Malhotra OP. Dicoumarol-induced prothrombins containing 6, 7, and 8 gamma-carboxyglutamic acid residues: isolation and characterization. Biochem Cell Biol. 1989;67:411–421
  27. Malhotra OP. Dicoumarol-induced 9-gamma-carboxyglutamic acid prothrombin: isolation and comparison with the 6-, 7-, 8-, and 10-gamma-carboxyglutamic acid isomers. Biochem Cell Biol. 1990;68:705–715
  28. Wallin R, Hutson SM. Warfarin and the vitamin K-dependent gamma-carboxylation system. Trends Mol Med. 2004;10:299–302
  29. Berkner KL. The vitamin K-dependent carboxylase. Annu Rev Nutr. 2005;25:127–149
  30. Wessler S, Gitel SN. Warfarin. From bedside to bench. N Engl J Med. 1984;311:645–652
  31. Zivelin A, Rao VM, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest. 1993;92:2131–2140
  32. Patel P, Weitz J, Brooker LA, Paes B, Mitchell L, Andrew M. Decreased thrombin activity of fibrin clots prepared in cord plasma compared with adult plasma. Pediatr Res. 1996;39:826–830
  33. O’ Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976;295:354–357
  34. Valente EJ, Trager WF. Anomalous chiroptical properties of warfarin and phenprocoumon. J Med Chem. 1978;21:141–143
  35. O’ Reilly RA. Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated enantiomorphs of racemic warfarin in man. N Engl J Med. 1980;302:33–35
  36. O’ Reilly RA, Trager WF, Rettie AE, Goulart DA. Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans. Clin Pharmacol Ther. 1987;42:290–294
  37. Toon S, Low LK, Gibaldi M, Trager WF, O’Reilly RA, Motley CH, et al. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther. 1986;39:15–24
  38. O’ Reilly RA. Lack of effect of fortified wine ingested during fasting and anticoagulant therapy. Arch Intern Med. 1981;141:458–464
  39. Bechtold H, Andrassy K, Jahnchen E, Koderisch J, Koderisch H, Weilemann LS, et al. Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins. Thromb Haemost. 1984;51:358–361
  40. Weitekamp MR, Aber R. Prolonged bleeding times and bleeding diathesis associated with moxalactam administration. JAMA. 1983;249:69–71
  41. Owens JC, Neely WB, Owen WR. Effect of sodium dextrothyroxine in patients receiving anticoagulants. N Engl J Med. 1962;266:76–79
  42. O’ Railly RA, Sahud MA, Robinson AJ. Studies on the interaction of warfarin and clofibrate in man. Thromb Diath Haemorrh. 1972;27:309–318
  43. Weibert RT, Lorentz SM, Townsend RJ, Cook CE, Klauber MR, Jagger PI. Effect of erythromycin in patients receiving long-term warfarin therapy. Clin Pharmacol. 1989;8:210–214
  44. Lorentz SM, Weibert RT. Potentiation of warfarin anticoagulation by topical testosterone ointment. Clin Pharmacol. 1985;4:332–334
  45. Rothschild BM. Hematologic perturbations associated with salicylate. Clin Pharmacol Ther. 1979;26:145–152
  46. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279:657–662
  47. Bell WR. Acetaminophen and warfarin: undesirable synergy. JAMA 998;279:702–703.
  48. Udall J. A Human sources and absorption of vitamin K in relation to anticoagulation stability. JAMA. 1965;194:127–129
  49. Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J. 1980;99:746–752
  50. Cazenave JP, Packham MA, Guccione MA, Mustardi JF. Effects of penicillin G on platelet aggregation, release, and adherence to collagen. Proc Soc Exp Biol Med. 1973;142:159–166
  51. Brown CH, Natelson EA, Bradshaw MW, Williams TW, Alfrey CP. The hemostatic defect produced by carbenicillin. N Engl J Med. 1974;291:265–270
  52. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med. 1994;121:676–683
  53. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Interactions of warfarin with drugs and food. Arch Intern Med. 2005;165:1095–1106
  54. Loebstein R, Yonath MD, Peleg D, Almong S, Rotenberg M, Lubetsky A, et al. Interindividual variability in sensitivity to warfarin–Nature or nurture?. Clin Pharmacol Ther. 2001;70:159–164
  55. Kamali F, Edwards C, Butler T, Wynne H. The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation. Thromb Haemost. 2000;84:39–42
  56. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet. 2000;356:1667–1671
  57. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics. 1996;6:429–439
  58. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics. 1996;6:341–349
  59. Rettie AE, Wienkers LC, Gonzales FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics. 1994;4:39–42
  60. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: 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
  61. 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
  62. Takanashi K, Tainaka H, Kobayashi K, Muramoto N, Shimizu T, Nasu K, et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Pharmacogenetics. 2000;10:95–104
  63. Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics. 1997;7:361–367
  64. Takahashi H, Kashima T, Nomizo I, Muramoto N, Shimizu T, Nasu K, 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
  65. 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
  66. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353:717–719
  67. Margaglione M, Colaizzo D, D’Andrea G, Brancaccio V, Ciampa A, Grandone E, et al. Thromb Haemost. 2000;84:775–778
  68. 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;96:1816–1819
  69. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287:1690–1698
  70. Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics. 2002;12:251–263
  71. Xie HG, Prasad HC, Kim RB, Stein CM. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev. 2002;54:1257–1270
  72. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb Res. 2007;120:1–10
  73. Yasar U, Aklillu E, Canaparo R, Sandberg M, Sayi J, Roh HK, et al. Analysis of CYP2C9*5 in Caucasian, Oriental and black-African populations. Eur J Clin Pharmacol. 2002;58:555–558
  74. Imai J, Ieiri I, Mamiya K, Miyahara S, Furuumi H, Nanba E, et al. Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics. 2000;10(1):85–89
  75. Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJ, Stein CM, et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol. 2001;60:382–387
  76. Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics. 2001;11:803–808
  77. Blaisdell J, Jorge-Nebert LF, Coulter S, Ferguson SS, Lee SJ, Chanas B, et al. Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics. 2004;14:527–537
  78. Tai G, Farin F, Rieder MJ, Dreisbach AW, Veenstra DL, Verlinde CL, et al. In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose. Pharmacogenet Genomics. 2005;15:475–481
  79. Si D, Guo Y, Zhang Y, Yang L, Zhou H, Zhong D. Identification of a novel variant CYP2C9 allele in Chinese. Pharmacogenetics. 2004;14:465–469
  80. Guo Y, Wang Y, Si D, Fawcett PJ, Zhong D, Zhou H. Catalytic activities of human cytochrome P450 2C9*1, 2C9*3 and 2C9*13. Xenobiotica. 2005;35:853–861
  81. Bae JW, Kim HK, Kim JH, Yang SI, Kim MJ, Jang CG, Park YS, Lee SY. Allele and genotype frequencies of CYP2C9 in a Korean population. Br J Clin Pharmacol. 2005 Oct;60(4):418–422.
  82. Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther. 2004;76:210–219
  83. DeLozier TC, Lee SC, Coulter SJ, Goh BC, Goldstein JA. Functional characterization of novel allelic variants of CYP2C9 recently discovered in southeast Asians. J Pharmacol Exp Ther. 2005;315:1085–1090
  84. Khon MH, Pelz HJ. A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. Blood. 2000;96:1996–1998
  85. Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J. Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood. 2002;100:3229–3232
  86. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–541
  87. Li T, Chang CY, Jin DY, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427:541–544
  88. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352:2285–2293
  89. Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost. 2005;93:23–26
  90. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood. 2005;106:135–140
  91. Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv. 2006;6:223–227
  92. D’Andrea G, D’Ambrosio RL, Di Perna PL, 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;105:645–649
  93. Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Gen. 2005;14:1745–1751
  94. 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;106:2329–2333
  95. Veenstra DL, You JH, Rieder MJ, Farin FM, Wilkerson HW, Blough DK, et al. Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics. 2005;15:687–691
  96. Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, 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;16:101–110
  97. Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Saito S, et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet. 2006;51:249–253
  98. Montes R, Ruiz de Gaona E, Martinez-Gonzales MA, Alberca I, Hermida J. The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol. 2006;133:183–187
  99. Reitsma PH, van der Heijden JF, Groot AP, Rosendaal FR, Büller HR. C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med. 2005;2:e 312
  100. Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic Complications in African-American and European-American Patients on Warfarin. Clin Pharmacol Ther. 2007;
  101. D’Ambrosio RL, D’Andrea G, Cafolla A, Faillace F, Margaglione M. A new vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with decreased stability of CYP2C9 enzyme. J Thromb Haemost. 2007;5:191–193
  102. Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood. 2007;109:2477–2480
  103. Goodstadt L, Ponting CP. Vitamin K epoxide reductase: homology, active site and catalytic mechanism. Trends Biochem Sci. 2004;29:289–292
  104. Rost S, Fregin A, Hünerberg M, Bevans CG, Müller CR, Oldenburg J. A site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb Haemost. 2005;94:780–786
  105. Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. 2005;94:773–779
  106. Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther. 2006;80:169–178
  107. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005;5:262–270
  108. Mannucci PM. Genetic control of anticoagulation. Lancet. 1999;353:688–689
  109. Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Müller CR, et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol. 1997;98:240–244
  110. Shikata E, Ieiri I, Ishiguro S, Aono H, Inoue K, Koide T, et al. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood. 2004;103:2630–2635
  111. D’Ambrosio RL, D’Andrea G, Cappucci F, Chetta M, Di Perna P, Brancaccio V, et al. Polymorphisms in factor II and factor VII genes modulate oral anticoagulation with warfarin. Haematologica. 2004;89:1510–1516
  112. Chen LY, Eriksson N, Gwilliam R, Bentley D, Deloukas P, Wadelius M. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing. Blood. 2005;106:3673–3674
  113. Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb. Res. 2007;120:181–186
  114. 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
  115. Vecsler M, Loebstein R, Almong S, Kurnik D, Goldman B, Halkin H, et al. 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
  116. Gonzales-Conejero R, Corral J, Roldan V, Ferrer F, Sánchez-Serrano I, Sánchez-Blanco JJ, et al. The genetic interaction between VKORC1 C1173T and calumenin A29809G modulates the anticoagulant response of acenocoumarol. J Thromb Haemost. 2007;5:1701–1706
  117. Loebstein R, Vecsler M, Kurnik D, Austerweil N, Gak E, Halkin H, et al. Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9. Clin Pharmacol Ther. 2005;77:365–372
  118. Visser LE, Trienekens PH, De Smet PA, Vulto AG, Hofman A, van Duijn CM, et al. Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genomics. 2005;15:69–74
  119. Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J. 2004;4:40–48
  120. Pollak ES, Hung HL, Godin W, Overton GC, High KA. Functional characterization of the human factor VII 5’-flanking region. J Biol Chem. 1996;271:1738–1747
  121. Spronk HM, Farah RA, Buchanan GR, Vermeer C, Soute BA. Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors. Blood. 2000;96:3650–3652
  122. Brenner B. Hereditary deficiency of vitamin K-dependent coagulation factors. Thromb Haemost. 2000;84:935–936
  123. Rost S, Fregin A, Koch D, Compes M, Müller CR, Oldenburg J. Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br J Haematol. 2004;126:546–549
  124. Pudota BN, Hommema EL, Hallgren KW, McNally BA, Lee S, Berkner KL. Identification of sequences within the gamma-carboxylase that represent a novel contact site with vitamin K-dependent proteins and that are required for activity. J Biol Chem. 2001;276:46878–46886
  125. Tie J, Wu SM, Jin D, Nicchitta CV, Stafford DW. A topological study of the human gamma-glutamyl carboxylase. Blood. 2000;96:973–978
  126. Cain D, Hutson SM, Wallin R. Assembly of the warfarin-sensitive vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem. 1997;272:29068–29075
  127. Kohnke H, Sorlin K, Granath G, Wadelius M. Warfarin dose related to apolipoprotein E (APOE) genotype. Eur J Clin Pharmacol. 2005;61:381–388
  128. Sconce EA, Daly AK, Khan TI, Wynne HA, Kamali F. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet. Genomics. 2006;16:609–611
  129. Kimmel SE, Christie J, Kealey C, Chen Z, Price M, Thorn CF, et al. Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans. Pharmacogenomics J. 2007;
  130. Caldwell MD, Berg RL, Zhang K, Glurich I, Schmelzer JR, Yale SH, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res. 2007;5:8–16
  131. Tong Y, Toshiyuki M. Warfarin dose and pharmacogenomics of CYP2C9 and VKORC1: rationale and perspectives. Thromb Res. 2007;120:1–10
  132. Wadelius M, Chen LY, Erikkson N, Bumpstead S, Ghori J, Wadelius C, et al. Association of warfarin dose with genes involved in its action and metabolism. Human Genet. 2007;121:23–34

PII: S0268-960X(07)00073-2

doi: 10.1016/j.blre.2007.11.004

Blood Reviews
Volume 22, Issue 3 , Pages 127-140 , May 2008

Article Tools

* Image Usage & Resolution