Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pharmacogenetics of warfarin: current status and future challenges

Abstract

Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

Abbreviations

ABCB1 :

ATP-binding cassette transporter B1 gene, P-glycoprotein gene or MDR1

APOE:

apolipoprotein E gene

CALU :

calumenin gene

CAR:

constitutive androstane receptor

CYP1A1:

cytochrome P450 1A1 gene

CYP1A2:

cytochrome P450 1A2 gene

CYP2A6:

cytochrome P450 2A6 gene

CYP2C18:

cytochrome P450 2C18 gene

CYP2C19:

cytochrome P450 2C19 gene

CYP2C8:

cytochrome P450 2C8 gene

CYP2C9:

cytochrome P450 2C9 gene

CYP3A4:

cytochrome P450 3A4 gene

CYP3A5:

cytochrome P450 3A5 gene

EPHX1 :

epoxide hydrolase 1, microsomal gene

F2 :

coagulation factor II gene or prothrombin gene

F5 :

coagulation factor V gene

F7 :

coagulation factor VII gene

F9 :

coagulation factor IX gene

F10 :

coagulation factor X gene

FII:

coagulation factor II or prothrombin

FIIa:

coagulation factor II activated or thrombin

FIX:

coagulation factor IX

FIXa:

coagulation factor IX activated

FV:

coagulation factor V

FVII:

coagulation factor VII

FVIIa:

coagulation factor VII activated

FX:

coagulation factor X

FXa:

coagulation factor X activated

GAS6 :

growth-arrest-specific 6 gene

GGCX :

gamma-glutamyl carboxylase gene

MDR1 :

multidrug resistance gene 1, P-glycoprotein gene or ABCB1

NQO1 :

NAD(P)H dehydrogenase, quinone 1 gene

NR1I2 :

pregnane X receptor gene

NR1I3 :

constitutive androstane receptor gene

ORM1 :

orosomucoid 1 gene or alpha-1-acid glycoprotein 1 gene

ORM2 :

orosomucoid 2 gene or alpha-1-acid glycoprotein 2 gene

PROC :

protein C gene

PROS1 :

protein S gene

PROZ :

protein Z gene

PT INR:

prothrombin time international normalized ratio

PXR:

pregnane X receptor

SERPINC1 :

anti-thrombin III gene

SNP:

single nucleotide polymorphism

VKORC1 :

vitamin K epoxide reductase complex subunit 1 gene

References

  1. Wadelius M, Sörlin 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.

    CAS  PubMed  Google Scholar 

  2. 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.

    CAS  PubMed  Google Scholar 

  3. Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A et al. Interindividual variability in sensitivity to warfarin – nature or nurture? Clin Pharmacol Ther 2001; 70: 159–164.

    CAS  PubMed  Google Scholar 

  4. Takahashi H, Echizen H . Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 2003; 3: 202–214.

    CAS  PubMed  Google Scholar 

  5. Higashi M, Veenstra D, Kondo L, Wittkowsky A, Srinouanprachanh S, Farin F et al. Association between CYP 2C9 genetic variants and anticoagulation-related outcomes during warfarin treatment. JAMA 2002; 287: 1690–1698.

    CAS  PubMed  Google Scholar 

  6. Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995; 5: 389–392.

    CAS  PubMed  Google Scholar 

  7. 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.

    CAS  PubMed  Google Scholar 

  8. Ogg MS, Brennan P, Meade T, Humphries SE . CYP2C9*3 allelic variant and bleeding complications. Lancet 1999; 354: 1124.

    CAS  PubMed  Google Scholar 

  9. Horton JD, Bushwick BM . Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999; 3: 635–646.

    Google Scholar 

  10. Aguilar MI, Hart R . Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev 2005; 3: CD001927.

  11. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ . Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472–477.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Linkins LA, Choi PT, Douketis JD . Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893–900.

    PubMed  Google Scholar 

  13. Fanikos J, Grasso-Correnti N, Shah R, Kucher N, Goldhaber SZ . Major bleeding complications in a specialized anticoagulation service. Am J Cardiol 2005; 96: 595–598.

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Palareti G, Legnani C . Warfarin withdrawal. Pharmacokinetic–pharmacodynamic considerations. Clin Pharmacokinet 1996; 30: 300–313.

    CAS  PubMed  Google Scholar 

  16. Otagiri M, Maruyama T, Imai T, Suenaga A, Imamura Y . A comparative study of the interaction of warfarin with human alpha 1-acid glycoprotein and human albumin. J Pharm Pharmacol 1987; 39: 416–420.

    CAS  PubMed  Google Scholar 

  17. Nakagawa T, Kishino S, Itoh S, Sugawara M, Miyazaki K . Differential binding of disopyramide and warfarin enantiomers to human alpha(1)-acid glycoprotein variants. Br J Clin Pharmacol 2003; 56: 664–669.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sussman N, Waltershied M, Butler T, Cali J, Riss T, Kelly J . The predictice nature of high throughput toxicity screening using a human hepatocyte cell line. Cell Notes 2002; 3: 7–10.

    Google Scholar 

  19. Ishikawa T, Hirano H, Onishi Y, Sakurai A, Tarui S . Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure–activity relationship analyses. Drug Metab Pharmacokinet 2004; 19: 1–14.

    CAS  PubMed  Google Scholar 

  20. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13: 481–494.

    CAS  PubMed  Google Scholar 

  21. Fischer V, Einolf HJ, Cohen D . Efflux transporters and their clinical relevance. Mini Rev Med Chem 2005; 5: 183–195.

    CAS  PubMed  Google Scholar 

  22. Chowbay B, Li H, David M, Cheung YB, Lee EJ . Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 2005; 60: 159–171.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kirchheiner J, Brockmoller J . Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1–16.

    CAS  PubMed  Google Scholar 

  24. Sanderson S, Emery J, Higgins J . CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7: 97–104.

    CAS  PubMed  Google Scholar 

  25. Linder MW . Genetic mechanisms for hypersensitivity and resistance to the anticoagulant Warfarin. Clin Chim Acta 2001; 308: 9–15.

    CAS  PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. Takahashi H, Echizen H . Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587–603.

    CAS  PubMed  Google Scholar 

  28. Kaminsky L, Zhang Z . Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67–74.

    CAS  PubMed  Google Scholar 

  29. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR . Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39–42.

    CAS  PubMed  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. 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.

    CAS  PubMed  Google Scholar 

  32. Aithal GP, Day CP, Kesteven PJ, Daly AK . Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–719.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. Margaglione M, Colaizzo D, D’Andrea G, Brancaccio V, Ciampa A, Grandone E et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775–778.

    CAS  PubMed  Google Scholar 

  35. Freeman BD, Zehnbauer BA, McGrath S, Borecki I, Buchman TG . Cytochrome P450 polymorphisms are associated with reduced warfarin dose. Surgery 2000; 128: 281–285.

    CAS  PubMed  Google Scholar 

  36. Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD . The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 2002; 194: 267–273.

    PubMed  Google Scholar 

  37. Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM . CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy. Clin Pharmacol Ther 2004; 75: 198–203.

    CAS  PubMed  Google Scholar 

  38. Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A . Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 2005; 78: 540–550.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. 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.

    CAS  PubMed  Google Scholar 

  41. Takahashi H, Kashima T, Nomizo Y, 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.

    CAS  PubMed  Google Scholar 

  42. Tabrizi AR, McGrath SD, Blinder MA, Buchman TG, Zehnbauer BA, Freeman BD . Extreme warfarin sensitivity in siblings associated with multiple cytochrome P450 polymorphisms. Am J Hematol 2001; 67: 144–146.

    CAS  PubMed  Google Scholar 

  43. Zhang Z, Fasco MJ, Huang Z, Guengerich FP, Kaminsky LS . Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 1995; 23: 1339–1346.

    CAS  PubMed  Google Scholar 

  44. 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.

    CAS  PubMed  Google Scholar 

  45. Grossman SJ, Herold EG, Drey JM, Alberts DW, Umbenhauer DR, Patrick DH et al. CYP1A1 specificity of Verlukast epoxidation in mice, rats, rhesus monkeys, and humans. Drug Metab Dispos 1993; 21: 1029–1036.

    CAS  PubMed  Google Scholar 

  46. Huang W, Lin YS, McConn II DJ, Calamia JC, Totah RA, Isoherranen N et al. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 2004; 32: 1434–1445.

    CAS  PubMed  Google Scholar 

  47. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J et al. Sequence diversity in CYP 3A promoters and characterization of the genetic basis of polymorphic CYP 3A5 expression. Nat Genet 2001; 27: 383–391.

    CAS  PubMed  Google Scholar 

  48. Daly AK, Aithal GP . Genetic regulation of warfarin metabolism and response. Semin Vasc Med 2003; 3: 231–238.

    PubMed  Google Scholar 

  49. Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD . The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70: 317–326.

    CAS  PubMed  Google Scholar 

  50. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM et al. St John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000; 97: 7500–7502.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102: 1016–1023.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen Y, Ferguson SS, Negishi M, Goldstein JA . Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther 2004; 308: 495–501.

    CAS  PubMed  Google Scholar 

  53. Geick A, Eichelbaum M, Burk O . Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 2001; 276: 14581–14587.

    CAS  PubMed  Google Scholar 

  54. Assenat E, Gerbal-Chaloin S, Larrey D, Saric J, Fabre JM, Maurel P et al. Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology 2004; 40: 951–960.

    CAS  PubMed  Google Scholar 

  55. Bell RG . Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K–epoxide cycle. Fed Proc 1978; 37: 2599–2604.

    CAS  PubMed  Google Scholar 

  56. Bell RG, Sadowski JA, Matschiner JT . Mechanism of action of warfarin. Warfarin and metabolism of vitamin K 1. Biochemistry 1972; 11: 1959–1961.

    CAS  PubMed  Google Scholar 

  57. Sadler JE . Medicine: K is for koagulation. Nature 2004; 427: 493–494.

    CAS  PubMed  Google Scholar 

  58. Shetty HG, Woods F, Routledge PA . The pharmacology of oral anticoagulants: implications for therapy. J Heart Valve Dis 1993; 2: 53–62.

    CAS  PubMed  Google Scholar 

  59. Hirsh J, Dalen J, Anderson D, Poller L, Bussey H, Ansell J et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114: 445S–469S.

    CAS  PubMed  Google Scholar 

  60. Sconce E, Khan T, Mason J, Noble F, Wynne H, Kamali F . Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005; 93: 872–875.

    CAS  PubMed  Google Scholar 

  61. Kohlmeier M, Salomon A, Saupe J, Shearer MJ . Transport of vitamin K to bone in humans. J Nutr 1996; 126: 1192S–1196S.

    CAS  PubMed  Google Scholar 

  62. Berkner KL, Runge KW . The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost 2004; 2: 2118–2132.

    CAS  PubMed  Google Scholar 

  63. Lamon-Fava S, Sadowski JA, Davidson KW, O’Brien ME, McNamara JR, Schaefer EJ . Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. Am J Clin Nutr 1998; 67: 1226–1231.

    CAS  PubMed  Google Scholar 

  64. Saupe J, Shearer MJ, Kohlmeier M . Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis. Am J Clin Nutr 1993; 58: 204–208.

    CAS  PubMed  Google Scholar 

  65. Rosand J, Hylek EM, O’Donnell HC, Greenberg SM . Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 2000; 55: 947–951.

    CAS  PubMed  Google Scholar 

  66. Kohnke H, Sörlin K, Granath G, Wadelius M . Warfarin dose related to apolipoprotein E (APOE) genotype. Eur J Clin Pharmacol 2005; 61: 381–388.

    CAS  PubMed  Google Scholar 

  67. 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.

    CAS  PubMed  Google Scholar 

  68. Kohnke H, Scordo MG, Pengo V, Padrini R, Wadelius M . Apolipoprotein E (APOE) and warfarin dosing in an Italian population. Eur J Clin Pharmacol 2005; 61: 781–783.

    PubMed  Google Scholar 

  69. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537–541.

    CAS  PubMed  Google Scholar 

  70. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW . Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541–544.

    CAS  PubMed  Google Scholar 

  71. 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.

    CAS  PubMed  Google Scholar 

  72. D’Andrea G, D’Ambrosio RL, Di Perna P, 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.

    PubMed  Google Scholar 

  73. 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.

    CAS  PubMed  Google Scholar 

  74. 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.

    CAS  PubMed  Google Scholar 

  75. 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 Genet 2005; 14: 1745–1751.

    CAS  PubMed  Google Scholar 

  76. 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.

    CAS  PubMed  Google Scholar 

  77. 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.

    CAS  PubMed  Google Scholar 

  78. 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.

    PubMed  Google Scholar 

  79. Vecsler M, Loebstein R, Almog 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.

    CAS  PubMed  Google Scholar 

  80. Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Shimomura H et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet 2006; 51: 249–253.

    CAS  PubMed  Google Scholar 

  81. 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.

    CAS  PubMed  Google Scholar 

  82. Lee SC, Ng SS, Oldenburg J, Chong PY, Rost S, Guo JY et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population. Clin Pharmacol Ther 2006; 79: 197–205.

    CAS  PubMed  Google Scholar 

  83. Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D 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: 291–302.

    CAS  PubMed  Google Scholar 

  84. 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.

    CAS  PubMed  Google Scholar 

  85. Reitsma PH, Heijden JF, Groot AP, Rosendaal FR, Buller HR . A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 2: e312.

    PubMed  PubMed Central  Google Scholar 

  86. 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.

    CAS  PubMed  Google Scholar 

  87. Morisseau C, Hammock BD . Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 2005; 45: 311–333.

    CAS  PubMed  Google Scholar 

  88. Guenthner TM, Cai D, Wallin R . Co-purification of microsomal epoxide hydrolase with the warfarin-sensitive vitamin K1 oxide reductase of the vitamin K cycle. Biochem Pharmacol 1998; 55: 169–175.

    CAS  PubMed  Google Scholar 

  89. 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.

    CAS  PubMed  Google Scholar 

  90. Ross D, Siegel D . NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics. Methods Enzymol 2004; 382: 115–144.

    CAS  PubMed  Google Scholar 

  91. Wallin R, Hutson S . Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation. J Biol Chem 1982; 257: 1583–1586.

    CAS  PubMed  Google Scholar 

  92. Rost S, Fregin A, Koch D, Compes M, Muller 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.

    CAS  PubMed  Google Scholar 

  93. Berkner KL . The vitamin K-dependent carboxylase. J Nutr 2000; 130: 1877–1880.

    CAS  PubMed  Google Scholar 

  94. Wu SM, Stafford DW, Frazier LD, Fu YY, High KA, Chu K et al. Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase. Blood 1997; 89: 4058–4062.

    CAS  PubMed  Google Scholar 

  95. Brenner B, Sanchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J . A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 1998; 92: 4554–4559.

    CAS  PubMed  Google Scholar 

  96. 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.

    CAS  PubMed  Google Scholar 

  97. 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.

    CAS  PubMed  Google Scholar 

  98. 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.

    CAS  PubMed  Google Scholar 

  99. 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.

    CAS  PubMed  Google Scholar 

  100. Broze Jr GJ . Protein Z-dependent regulation of coagulation. Thromb Haemost 2001; 86: 8–13.

    CAS  PubMed  Google Scholar 

  101. 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.

    PubMed  Google Scholar 

  102. Kristensen SR . Warfarin treatment of a patient with coagulation factor IX propeptide mutation causing warfarin hypersensitivity. Blood 2002; 100: 2676–2677.

    CAS  PubMed  Google Scholar 

  103. van der Heijden JF, Rekke B, Hutten BA, van der Meer FJ, Remkes MG, Vermeulen M et al. Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX. J Thromb Haemost 2004; 2: 1104–1109.

    CAS  PubMed  Google Scholar 

  104. Weiss P, Soff GA, Halkin H, Seligsohn U . Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy. Thromb Res 1987; 45: 783–790.

    CAS  PubMed  Google Scholar 

  105. Vigano S, Mannucci PM, Solinas S, Bottasso B, Mariani G . Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol 1984; 57: 213–220.

    CAS  PubMed  Google Scholar 

  106. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI . Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 1984; 101: 59–60.

    CAS  PubMed  Google Scholar 

  107. Chan YC, Valenti D, Mansfield AO, Stansby G . Warfarin induced skin necrosis. Br J Surg 2000; 87: 266–272.

    CAS  PubMed  Google Scholar 

  108. Dahlback B . Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases. J Intern Med 2005; 257: 209–223.

    PubMed  Google Scholar 

  109. Larsen TB, Lassen JF, Dahler-Eriksen BS, Petersen PH, Brandslund I . Effect of anticoagulant therapy on the hypercoagulable state in patients carrying the factor V Arg506Gln mutation. Thromb Res 1998; 92: 157–162.

    CAS  PubMed  Google Scholar 

  110. Andersson T, Flockhart DA, Goldstein DB, Huang SM, Kroetz DL, Milos PM et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005; 78: 559–581.

    CAS  PubMed  Google Scholar 

  111. Hillman MA, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Glurich I et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 3: 137–145.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Keavney B, McKenzie C, Parish S, Palmer A, Clark S, Youngman L et al. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet 2000; 355: 434–442.

    CAS  PubMed  Google Scholar 

  113. Shine D, Patel J, Kumar J, Malik A, Jaeger J, Maida M et al. A randomized trial of initial warfarin dosing based on simple clinical criteria. Thromb Haemost 2003; 89: 297–304.

    CAS  PubMed  Google Scholar 

  114. Aithal G, Day C, Kesteven P, Daly A . Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–719.

    CAS  PubMed  Google Scholar 

  115. Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ . Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91: 1123–1128.

    CAS  PubMed  Google Scholar 

  116. Fihn S, Callahan C, Martin D, McDonell M, Henikoff J, White R . The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970–979.

    CAS  PubMed  Google Scholar 

  117. Ripley TL, Havrda DE, Blevins S, Culkin D . Early evaluation of hematuria in a patient receiving anticoagulant therapy and detection of malignancy. Pharmacotherapy 2004; 24: 1638–1640.

    PubMed  Google Scholar 

  118. Muhlau M, Schlegel J, Von Einsiedel HG, Conrad B, Sander D . Multiple progressive intracerebral hemorrhages due to an angiosarcoma: a case report. Eur J Neurol 2003; 10: 741–742.

    CAS  PubMed  Google Scholar 

  119. Nurden AT, Nurden P . Inherited disorders of platelets: an update. Curr Opin Hematol 2006; 13: 157–162.

    CAS  PubMed  Google Scholar 

  120. You JH, Chan FW, Wong RS, Cheng G . The potential clinical and economic outcomes of pharmacogenetics-oriented management of warfarin therapy – a decision analysis. Thromb Haemost 2004; 92: 590–597.

    CAS  PubMed  Google Scholar 

  121. Woelderink A, Ibarreta D, Hopkins MM, Rodriguez-Cerezo E . The current clinical practice of pharmacogenetic testing in Europe: TPMT and HER2 as case studies. Pharmacogenomics J 2006; 6: 3–7.

    CAS  PubMed  Google Scholar 

  122. Gardiner SJ, Begg EJ . Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice? Pharmacogenet Genomics 2005; 15: 365–369.

    CAS  PubMed  Google Scholar 

  123. Fitzmaurice DA, Hobbs FD, Delaney BC, Wilson S, McManus R . Review of computerized decision support systems for oral anticoagulation management. Br J Haematol 1998; 102: 907–909.

    CAS  PubMed  Google Scholar 

  124. Yang DT, Robetorye RS, Rodgers GM . Home prothrombin time monitoring: a literature analysis. Am J Hematol 2004; 77: 177–186.

    PubMed  Google Scholar 

  125. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293: 690–698.

    PubMed  Google Scholar 

  126. Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005; 93: 700–705.

    CAS  PubMed  Google Scholar 

  127. Leung AY, Chow HC, Kwong YL, Lie AK, Fung AT, Chow WH et al. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 2001; 98: 2584–2587.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The support of the UK Department of Health, which is funding the prospective UK warfarin pharmacogenetics study, is gratefully acknowledged. The Uppsala warfarin study is supported by the Swedish Society of Medicine, Foundation for Strategic Research, Heart and Lung Foundation and the Clinical Research Support (ALF) at Uppsala University. The support of David Bentley and the Wellcome Trust Sanger Institute is acknowledged. The sponsors had no role in the writing of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Wadelius.

Additional information

Duality of Interest

None.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wadelius, M., Pirmohamed, M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 7, 99–111 (2007). https://doi.org/10.1038/sj.tpj.6500417

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500417

Keywords

This article is cited by

Search

Quick links