Pharmacogenetics of vitamin K antagonists: Useful or hype?

Clinical Chemistry and Laboratory Medicine

Volumn 47, Issue 5, 2009, Pages 503-515

  Lippi, Giuseppe ^a,d   Franchini, Massimo ^b   Favaloro, Emmanuel J ^c  

^a UNIVERSITY OF VERONA   (Italy)

^b UNIVERSITY HOSPITAL OF PARMA   (Italy)

^c WESTMEAD HOSPITAL   (Australia)

^d UNIVERSITY HOSPITAL OF VERONA   (Italy)

Author keywords

Oral anticoagulant therapy (OAT); Pharmacogenetics; Therapeutic drug monitoring; Vitamin K; Warfarin

Indexed keywords

ACENOCOUMAROL; ANTIVITAMIN K; BLOOD CLOTTING FACTOR 10; CYTOCHROME P450 2C9; OXIDOREDUCTASE; SYNTROM; THROMBIN; UNCLASSIFIED DRUG; VITAMIN K GROUP; WARFARIN;

AGE; ANTICOAGULANT THERAPY; ANTICOAGULATION; BLEEDING; BODY MASS; CARBOXYLATION; COMORBIDITY; DIETARY INTAKE; DOSE RESPONSE; DRUG ABSORPTION; DRUG COMPETITION; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; ETHICS; GENE; GENETIC POLYMORPHISM; GENETICS; HUMAN; OUTCOME ASSESSMENT; PHARMACOGENETICS; PHILOSOPHY; PRIORITY JOURNAL; PROPHYLAXIS; QUALITATIVE ANALYSIS; QUALITY OF LIFE; RACE; REVIEW; RISK ASSESSMENT; SINGLE NUCLEOTIDE POLYMORPHISM; SOCIAL ASPECT; THROMBOSIS; VKOR GENE;

ALGORITHMS; ANTICOAGULANTS; ARYL HYDROCARBON HYDROXYLASES; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MIXED FUNCTION OXYGENASES; PHARMACOGENETICS; POLYMORPHISM, GENETIC; VITAMIN K;

EID: 67649204395     PISSN: 14346621     EISSN: 14374331     Source Type: Journal    
DOI: 10.1515/CCLM.2009.140     Document Type: Review

References (89)

1. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest 2008; 133(6 Suppl):160S-198S.
2. Manolopoulos VG. Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice. Clin Chem Lab Med 2007;45:801-14.
3. Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, et al. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab 2008;9: 738-84.
4. Lippi G, Franchini M, Montagnana M, Guidi GC. Genomics and proteomics in venous thromboembolism: building a bridge toward a rational personalized medicine framework. Semin Thromb Hemost 2007;33:759-70.
5. Oscarson M. Pharmacogenetics of drug metabolising enzymes: importance for personalised medicine. Clin Chem Lab Med 2003;41:573-80.
6. Boissel JP, Gueyffier F, Cucherat M, Bricca G. Pharmacogenetics and responders to a therapy: theoretical background and practical problems. Clin Chem Lab Med 2003;41:564-72.
7. Siest G, Ferrari L, Accaoui MJ, Batt AM, Visvikis S. Pharmacogenomics of drugs affecting the cardiovascular system. Clin Chem Lab Med 2003;41:590-9.
8. Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008;141:757-63.
9. Oldenburg J, Bevans CG, Müller CR, Watzka M. Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal 2006;8:347-53.
10. 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;427:537-41.
11. Au N, Rettie AE. Pharmacogenomics of 4-hydroxycoumarin anticoagulants. Drug Metab Rev 2008;40:355-75.
12. 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;106:135-40.
13. 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;352:2285-93.
14. 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.
15. Zhu Y, Shennan M, Reynolds KK, Johnson NA, Herrnberger MR, Valdes R Jr, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639G>A) and CYP2C9 genotypes. Clin Chem 2007;53:1199-205.
16. 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;120:181-6.
17. Caldwell MD, Berg RL, Zhang KQ, Glurich I, Schmelzer JR, Yale SH, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007;5:8-16.
18. 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;112:1013-21.
19. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008;358:999-1008.
20. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009;113:784-92.
21. 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; 109:2477-80.
22. Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008;112:1022-7.
23. 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 2008;83: 312-21.
24. Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 2008;64:889-94.
25. Kim HS, Lee SS, Oh M, Jang YJ, Kim EY, Han IY, et al. Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement. Pharmacogenet Genomics 2009;19:103-12.
26. Borgiani P, Ciccacci C, Forte V, Romano S, Federici G, Novelli G. Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics 2007;8:1545-50.
27. Cho HJ, Sohn KH, Park HM, Lee KH, Choi B, Kim S, et al. Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients. Pharmacogenomics 2007;8:329-37.
28. 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. J Am Med Assoc 2002;287:1690-8.
29. Topić E, Stefanović M, Samardzija M. Association between the CYP2C9 polymorphism and the drug metabolism phenotype. Clin Chem Lab Med 2004;42: 72-8.
30. Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of over anticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 2005;78:540-50.
31. Li T, Lange LA, Li X, Susswein L, Bryant B, Malone R, et al. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 2006; 43:740-4.
32. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008;83:460-70.
33. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008;111:4106-12.
34. 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 2008;8:53-60.
35. Saraeva RB, Paskaleva ID, Doncheva E, Eap CB, Ganev VS. Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements. J Clin Pharm Ther 2007;32:641-9.
36. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360:753-64.
37. Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, et al. 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;22:191-7.
38. 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 war-farin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006;16:101-10.
39. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Couma-Gen investigators. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-70.
40. 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.
41. Michaud V, Vanier MC, Brouillette D, Roy D, Verret L, Noel N, et al. Combination of phenotype assessments and CYP2C9-VKORC1 polymorphisms in the determination of warfarin dose requirements in heavily medicated patients. Clin Pharmacol Ther 2008;83:740-8.
42. Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: aprospective study in Chinese patients. Pharmacogenet Genomics 2009 Jan 27. [Epub ahead of print].
43. Yoshizawa M, Hayashi H, Tashiro Y, Sakawa S, Moriwaki H, Akimoto T, et al. Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res 2009 Jan 7. [Epub ahead of print].
44. 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;106:135-40.
45. Johnson JA. Ethnic differences in cardiovascular drug response: potential contribution of pharmacogenetics. Circulation 2008;118:1383-93.
46. Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008;392:1093-108.
47. 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. Biochemistry 1990;29:11280-92.
48. 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;5:54-9.
49. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67-74.
50. 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;353:717-9.
51. Takahashi H, Kashima T, Nomoto S, Iwade K, Tainaka H, Shimizu T, et al. Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics 1998;8:365-73.
52. 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.
53. Kohlmeier M, Salomon A, Saupe J, Shearer MJ. Transport of vitamin K to bone in humans. J Nutr 1996; 126:S1192-6.
54. Beinema M, Brouwers JR, Schalekamp T, Wilffert B. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100:1052-7.
55. US Food and Drug Administration. FDA clears genetic lab test for warfarin sensitivity. Press release of the food and drug administration, September 17, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01701.html. Accessed 8 February 2008.
56. Hulse ML. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996;16:1009-17.
57. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676-83.
58. Vazquez SR, Rondina MT, Pendleton RC. Azathioprine-induced warfarin resistance. Ann Pharmacother 2008;42: 1118-23.
59. Harrington DJ, Gorska R, Wheeler R, Davidson S, Murden S, Morse C, et al. Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1. J Thromb Haemost 2008;6:1663-70.
60. 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;93:23-6.
61. Ainle FN, Mumford A, Tallon E, McCarthy D, Murphy K. A vitamin K epoxide reductase complex subunit 1 mutation in an Irish patient with warfarin resistance. Ir J Med Sci 2008;177:159-6.
62. 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; 109:2477-80.
63. Lippi G, Salvagno GL, Guidi GC. Genetic factors for warfarin dose prediction. Clin Chem 2007;53:1721-2.
64. Lippi G, Salvagno GL, Guidi GC. Genetic analysis to prevent warfarin complications. CMAJ 2007;177:377.
65. McClain MR, Palomaki GE, Piper M, Haddow JE. A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genet Med 2008;10:89-98.
66. Williams LO, Cole EC, Lubin IM, Iglesias NI, Jordan RL, Elliott LE. Quality assurance in human molecular genetics testing: status and recommendations. Arch Pathol Lab Med 2003;127:1353-8.
67. Chen B, O'Connell CD, Boone DJ, Amos JA, Beck JC, Chan MM, et al. Developing a sustainable process to provide quality control materials for genetic testing. Genet Med 2005;7:534-49.
68. Lai E, Bowman C, Bansal A, Hughes A, Mosteller M, Roses AD. Medical applications of haplotype-based SNP maps: learning to walk before we run. Nat Genet 2002;32:353.
69. Wadelius M. Pro: use of pharmacogenetics in guiding treatment with warfarin. Clin Chem 2009 Jan 30. [Epub ahead of print].
70. McWilliam A, Lutter R, Nardinelli C. Health care savings from personalizing medicine using genetic testing: the case of warfarin. AEI-Brooking Joint Center for Regulatory Studies Working Paper 06-23, November 2006. http://www.aei-brookings.org/publications/abstract.php?pid=1127. Accessed 8 February 2009.
71. Veenstra DL. The cost-effectiveness of warfarin pharmacogenomics. J Thromb Haemost 2007;5:1974-5.
72. Bussey HI, Wittkowsky AK, Hylek EM, Walker MB. Genetic testing for warfarin dosing? Not yet ready for prime time. Pharmacotherapy 2008;28:141-3.
73. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with non-valvular atrial fibrillation. Ann Intern Med 2009;150:73-83.
74. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-effectiveness in health and medicine, 1st ed. New York: Oxford University Press, 1996.
75. Eckman MH, Wong LK, Soo YO, Lam W, Yang SR, Greenberg SM, et al. Patient-specific decision-making for warfarin therapy in non-valvular atrial fibrillation: how will screening with genetics and imaging help? Stroke 2008;39:3308-15.
76. Hynicka LM, Cahoon WD Jr, Bukaveckas BL. Genetic testing for warfarin therapy initiation. Ann Pharmacother 2008;42:1298-303.
77. Vlad MO, Corlan AD, Morán F, Oefner P, Ross J. Incremental parameter evaluation from incomplete data with application to the population pharmacology of anticoagulants. Proc Natl Acad Sci USA 2008;105:4627-32.
78. Favaloro EJ. Diagnostic issues in thrombophilia: a laboratory scientist's view. Semin Thromb Hemost 2005;31: 11-6.
79. Plebani M, Marincola FM. Research translation: a new frontier for clinical laboratories. Clin Chem Lab Med 2006;44:1303-12.
80. Plebani M. The changing scenario in laboratory medicine and the role of laboratory professionals in translational medicine. Clin Chim Acta 2008;393:23-6.
81. Guidi GC, Lippi G. Will "personalized medicine" need personalized laboratory approach? Clin Chim Acta 2009; 400:25-9.
82. Padrini R, Ferrari M. Pharmacogenetics. N Engl J Med 2003;348:2041-3.
83. Rumilla K, Chen D, Baudhuin LM. Pharmacogenetics in hemostasis: Friend or foe? Semin Thromb Hemost, 2009, in press.
84. Enström C, Osman A, Lindahl TL. A genotyping method for VKORC1 1173C>T by Pyrosequencing technology. Scand J Clin Lab Invest 2008;68:427-30.
85. Huang SW, Li Q, Zhu SY, Li L, Xiong F, Jia YK, et al. SYBR Green-based real-time PCR assay for detection of VKORC1 and CYP2C9 polymorphisms that modulate warfarin dose requirement. Clin Chem Lab Med 2009; 47:26-31.
86. Aomori T, Yamamoto K, Oguchi-Katayama A, Kawai Y, Ishidao T, Mitani Y, et al. Rapid single-nucleotide polymorphism detection of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKORC1) Genes for the warfarin dose adjustment by the SMart-Amplification Process Version 2. Clin Chem 2009 Jan 30. [Epub ahead of print].
87. Fareed J, Hoppensteadt DA, Fareed D, Demir M, Wahi R, Clarke M, et al. Survival of heparins, oral anticoagulants, and aspirin after the year 2010. Semin Thromb Hemost 2008;34:58-73.
88. Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Hemost 2008;34:39-57.
89. Franchini M, Lippi G. Antagonists of activated factor X and thrombin: innovative antithrombotic agents. Curr Vasc Pharmacol 2007;5:121-8.