Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin

Seminars in Thrombosis and Hemostasis

Volumn 38, Issue 8, 2012, Pages 893-904

  Fung, Erik ^a,b   Patsopoulos, Nikolaos A ^c,d,e   Belknap, Steven M ^f   O'Rourke, Daniel J ^a,b,g   Robb, John F ^a,b   Anderson, Jeffrey L ^h,i   Shworak, Nicholas W ^a,b   Moore, Jason H ^b,j  

^a DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

^b DARTMOUTH MEDICAL SCHOOL   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^f NORTHWESTERN MEMORIAL HOSPITAL   (United States)

^g VA MEDICAL CENTER   (United States)

^h INTERMOUNTAIN MEDICAL CENTER   (United States)

ⁱ UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^j DARTMOUTH COLLEGE   (United States)

more..

Author keywords

personalized medicine; pharmacogenetics; polymorphisms; warfarin

Indexed keywords

ACENOCOUMAROL; APIXABAN; CYTOCHROME P450 2C9; DABIGATRAN; OXIDOREDUCTASE; RIVAROXABAN; UNCLASSIFIED DRUG; VITAMIN K EPOXIDE REDUCTASE COMPLEX UNIT 1; WARFARIN;

ALLELE; ARTICLE; COST EFFECTIVENESS ANALYSIS; DOSE RESPONSE; DRUG DOSE TITRATION; ETHNICITY; GENETIC VARIABILITY; HUMAN; INTERNATIONAL NORMALIZED RATIO; PHARMACOGENETICS; PRIORITY JOURNAL; TREATMENT RESPONSE;

ANTICOAGULANTS; ARYL HYDROCARBON HYDROXYLASES; GENETIC VARIATION; GENOTYPE; HUMANS; INTERNATIONAL NORMALIZED RATIO; MIXED FUNCTION OXYGENASES; WARFARIN;

EID: 84868546159     PISSN: 00946176     EISSN: 10989064     Source Type: Journal    
DOI: 10.1055/s-0032-1328891     Document Type: Article

References (168)

1. Stroke Prevention in Atrial Fibrillation Investigators Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet: 1996; 348 9028 633 638
2. Hart R. G., Pearce L. A., Aguilar M. I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med: 2007; 146 12 857 867 (Pubitemid 351650486)
3. Petersen P., Boysen G., Godtfredsen J., Andersen E. D., Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet: 1989; 1 8631 175 179 (Pubitemid 19038801)
4. Avorn J. The relative cost-effectiveness of anticoagulants: obvious, except for the cost and the effectiveness. Circulation: 2011; 123 22 2519 2521
5. Friberg L., Rosenqvist M., Lip G. Y. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation: 2012; 125 19 2298 2307
6. Flockhart D. A., O'Kane D., Williams M. S., et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med: 2008; 10 2 139 150 (Pubitemid 351271726)
7. Wysowski D. K., Nourjah P., Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med: 2007; 167 13 1414 1419 (Pubitemid 47052441)
8. Hylek E. M., Chang Y. C., Skates S. J., Hughes R. A., Singer D. E. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med: 2000; 160 11 1612 1617 (Pubitemid 30367900)
9. Merli G. J., Tzanis G. Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio? J Thromb Thrombolysis: 2009; 27 3 293 299
10. Oake N., Jennings A., Forster A. J., Fergusson D., Doucette S., van Walraven C. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ: 2008; 179 3 235 244
11. Cooper G. M., Johnson J. A., Langaee T. Y., et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood: 2008; 112 4 1022 1027
12. Kamali F., Wynne H. Pharmacogenetics of warfarin. Annu Rev Med: 2010; 61 63 75
13. Skov J., Bladbjerg E. M., Rasmussen M. A., Sidelmann J. J., Leppin A., Jespersen J. Genetic, clinical and behavioural determinants of vitamin K-antagonist dose - explored through multivariable modelling and visualization. Basic Clin Pharmacol Toxicol: 2011; 67 11 1169 1174
14. Takeuchi F., McGinnis R., Bourgeois S., et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet: 2009; 5 3 e1000433
15. Shine D., Patel J., Kumar J., et al. A randomized trial of initial warfarin dosing based on simple clinical criteria. Thromb Haemost: 2003; 89 2 297 304 (Pubitemid 36227282)
16. Anderson J. L., Horne B. D., Stevens S. M., et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation: 2007; 116 22 2563 2570 (Pubitemid 350179221)
17. Anderson J. L., Horne B. D., Stevens S. M., et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation: 2012; 125 16 1997 2005
18. Gong I. Y., Tirona R. G., Schwarz U. I., et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood: 2011; 118 11 3163 3171
19. Epstein R. S., Moyer T. P., Aubert R. E., et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol: 2010; 55 25 2804 2812
20. Klein T. E., Altman R. B., Eriksson N., et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med: 2009; 360 8 753 764. Erratum in N Engl J Med 2009;361(16):1613
21. Rieder M. J., Reiner A. P., Gage B. F., et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med: 2005; 352 22 2285 2293 (Pubitemid 40740552)
22. Sconce E. A., Khan T. I., Wynne H. A., 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 7 2329 2333 (Pubitemid 41510803)
23. Lam M. P., Cheung B. M. The pharmacogenetics of the response to warfarin in Chinese. Br J Clin Pharmacol: 2012; 73 3 340 347
24. Limdi N. A., Wadelius M., Cavallari L., et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood: 2010; 115 18 3827 3834
25. Scott S. A., Jaremko M., Lubitz S. A., Kornreich R., Halperin J. L., Desnick R. J. CYP2C98 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics: 2009; 10 8 1243 1255
26. Wadelius M., Chen L. Y., Lindh J. D., et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood: 2009; 113 4 784 792
27. Chan S. L., Suo C., Lee S. C., et al. Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia. Pharmacogenomics J: 2011; 12 4 312 318
28. Shuen A. Y., Wong B. Y., Fu L., Selby R., Cole D. E. Evaluation of the warfarin-resistance polymorphism, VKORC1 Asp36Tyr, and its effect on dosage algorithms in a genetically heterogeneous anticoagulant clinic. Clin Biochem: 2012; 45 6 397 401
29. Poller L. International Normalized Ratios (INR): the first 20 years. J Thromb Haemost: 2004; 2 6 849 860 (Pubitemid 40185727)
30. Kirkwood T. B. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Thromb Haemost: 1983; 49 3 238 244 (Pubitemid 13060101)
31. Fennerty A., Dolben J., Thomas P., et al. Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed): 1984; 288 6426 1268 1270 (Pubitemid 14117132)
32. Crowther M. A., Harrison L., Hirsh J. Randomized trial of warfarin nomograms. Ann Intern Med: 2004; 140 6 490, author reply 491-492
33. Kovacs M. J., Rodger M., Anderson D. R., et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med: 2003; 138 9 714 719
34. Roberts G. W., Druskeit T., Jorgensen L. E., et al. Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty's protocol. Aust N Z J Med: 1999; 29 5 731 736 (Pubitemid 29530192)
35. Tait R. C., Sefcick A. A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation. Br J Haematol: 1998; 101 3 450 454 (Pubitemid 28266936)
36. Li-Saw-Hee F. L., Blann A. D., Lip G. Y. Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation. Stroke: 2000; 31 4 828 833 (Pubitemid 30198423)
37. Holbrook A. M., Pereira J. A., Labiris R., et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med: 2005; 165 10 1095 1106 (Pubitemid 40720733)
38. Dang M. T., Hambleton J., Kayser S. R. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother: 2005; 39 6 1008 1012 (Pubitemid 40695964)
39. Gurwitz J. H., Avorn J., Ross-Degnan D., Choodnovskiy I., Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med: 1992; 116 11 901 904 (Pubitemid 23034781)
40. McClain M. R., Palomaki G. E., Piper M., Haddow J. E. 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 2 89 98 (Pubitemid 351271719)
41. Wynne H. A., Kamali F., Edwards C., Long A., Kelly P. Effect of ageing upon warfarin dose requirements: a longitudinal study. Age Ageing: 1996; 25 6 429 431 (Pubitemid 26418170)
42. Gage B. F., Eby C., Johnson J. A., et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther: 2008; 84 3 326 331
43. Jonas D. E., McLeod H. L. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci: 2009; 30 7 375 386
44. Burmester J. K., Berg R. L., Glurich I., Yale S. H., Schmelzer J. R., Caldwell M. D. Absence of novel CYP4F2 and VKORC1 coding region DNA variants in patients requiring high warfarin doses. Clin Med Res: 2011; 9 3-4 119 124
45. Scott S. A., Patel M., Martis S., et al. Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU. Pharmacogenomics: 2012; 13 3 297 307
46. Moyer T. P., O'Kane D. J., Baudhuin L. M., et al. Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Mayo Clin Proc: 2009; 84 12 1079 1094
47. Rettie A. E., Korzekwa K. R., Kunze K. L., 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 1 54 59
48. Rettie A. E., Jones J. P. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol: 2005; 45 477 494 (Pubitemid 40267790)
49. de Morais S. M., Schweikl H., Blaisdell J., Goldstein J. A. Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18. Biochem Biophys Res Commun: 1993; 194 1 194 201 (Pubitemid 23237919)
50. Stubbins M. J., Harries L. W., Smith G., Tarbit M. H., Wolf C. R. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics: 1996; 6 5 429 439 (Pubitemid 26380099)
51. Haining R. L., Hunter A. P., Veronese M. E., Trager W. F., Rettie A. E. 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 2 447 458 (Pubitemid 26304913)
52. Rettie A. E., Wienkers L. C., Gonzalez F. J., Trager W. F., Korzekwa K. R. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics: 1994; 4 1 39 42 (Pubitemid 24106122)
53. Margaglione M., Colaizzo D., D'Andrea G., et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost: 2000; 84 5 775 778
54. 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 1819 (Pubitemid 30661066)
55. Linder M. W., Bon Homme M., Reynolds K. K., et al. Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy. Clin Chem: 2009; 55 10 1861 1868
56. Aithal G. P., Day C. P., Kesteven P. J., Daly A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet: 1999; 353 9154 717 719 (Pubitemid 29103806)
57. Furuya H., Fernandez-Salguero P., Gregory W., et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics: 1995; 5 6 389 392 (Pubitemid 26010117)
58. Higashi M. K., Veenstra D. L., Kondo L. M., et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA: 2002; 287 13 1690 1698 (Pubitemid 34289221)
59. Hillman M. A., Wilke R. A., Caldwell M. D., Berg R. L., Glurich I., Burmester J. K. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics: 2004; 14 8 539 547 (Pubitemid 39100005)
60. Steward D. J., Haining R. L., Henne K. R., et al. Genetic association between sensitivity to warfarin and expression of CYP2C93. Pharmacogenetics: 1997; 7 5 361 367 (Pubitemid 27427545)
61. Imai J., Ieiri I., Mamiya K., 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 (Pubitemid 30142817)
62. Cavallari L. H., Langaee T. Y., Momary K. M., et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther: 2010; 87 4 459 464
63. Dickmann L. J., Rettie A. E., Kneller M. B., et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C95) expressed among African Americans. Mol Pharmacol: 2001; 60 2 382 387 (Pubitemid 32678304)
64. Scott S. A., Khasawneh R., Peter I., Kornreich R., Desnick R. J. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics: 2010; 11 6 781 791
65. DeLozier T. C., Lee S. C., Coulter S. J., Goh B. C., Goldstein J. A. Functional characterization of novel allelic variants of CYP2C9 recently discovered in southeast Asians. J Pharmacol Exp Ther: 2005; 315 3 1085 1090 (Pubitemid 41635394)
66. Oldenburg J., Marinova M., Müller-Reible C., Watzka M. The vitamin K cycle. Vitam Horm: 2008; 78 35 62
67. Rasmussen M. A., Skov J., Bladbjerg E. M., Sidelmann J. J., Vamosi M., Jespersen J. Multivariate analysis of the relation between diet and warfarin dose. Eur J Clin Pharmacol: 2012; 68 3 321 328
68. 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 3, Suppl 204S 233S. Erratum in Chest 2005;127(1):415-416 (Pubitemid 39297955)
69. Stafford D. W. The vitamin K cycle. J Thromb Haemost: 2005; 3 8 1873 1878 (Pubitemid 41716574)
70. Oldenburg J., Watzka M., Rost S., Müller C. R. VKORC1: molecular target of coumarins. J Thromb Haemost: 2007; 5 01 1 6 (Pubitemid 46958810)
71. Wang D., Chen H., Momary K. M., Cavallari L. H., Johnson J. A., 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
72. Rost S., Fregin A., Ivaskevicius V., et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature: 2004; 427 6974 537 541 (Pubitemid 38209110)
73. Li T., Chang C. Y., Jin D. Y., Lin P. J., Khvorova A., Stafford D. W. Identification of the gene for vitamin K epoxide reductase. Nature: 2004; 427 6974 541 544 (Pubitemid 38209111)
74. Harrington D. J., Gorska R., Wheeler R., et al. Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1. J Thromb Haemost: 2008; 6 10 1663 1670
75. Moreau C., Pautas E., Gouin-Thibault I., et al. Predicting the warfarin maintenance dose in elderly inpatients at treatment initiation: accuracy of dosing algorithms incorporating or not VKORC1/CYP2C9 genotypes. J Thromb Haemost: 2011; 9 4 711 718
76. D'Andrea G., D'Ambrosio R. L., Di Perna P., et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood: 2005; 105 2 645 649 (Pubitemid 40070748)
77. Loebstein R., Dvoskin I., Halkin H., et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood: 2007; 109 6 2477 2480 (Pubitemid 46425891)
78. Marsh S., King C. R., Porche-Sorbet R. M., Scott-Horton T. J., Eby C. S. Population variation in VKORC1 haplotype structure. J Thromb Haemost: 2006; 4 2 473 474
79. Watzka M., Geisen C., Bevans C. G., et al. Thirteen novel VKORC1 mutations associated with oral anticoagulant resistance: insights into improved patient diagnosis and treatment. J Thromb Haemost: 2011; 9 1 109 118
80. Aquilante C. L., Langaee T. Y., Lopez L. 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
81. Carlquist J. F., Horne B. D., Muhlestein J. B., 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 3 191 197 (Pubitemid 44857780)
82. Pautas E., Moreau C., Gouin-Thibault I., et al. Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clin Pharmacol Ther: 2010; 87 1 57 64
83. Takanashi K., Tainaka H., Kobayashi K., Yasumori T., Hosakawa M., Chiba K. CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics: 2000; 10 2 95 104 (Pubitemid 30193071)
84. Wadelius M., Chen L. Y., Downes K., et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J: 2005; 5 4 262 270 (Pubitemid 41131718)
85. Wadelius M., Sörlin K., Wallerman O., et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J: 2004; 4 1 40 48 (Pubitemid 38256604)
86. Cho H. J., On Y. K., Bang O. Y., et al. Development and comparison of a warfarin-dosing algorithm for Korean patients with atrial fibrillation. Clin Ther: 2011; 33 10 1371 1380
87. Lenzini P., Wadelius M., Kimmel S., et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther: 2010; 87 5 572 578
88. Ferder N. S., Eby C. S., Deych E., et al. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost: 2010; 8 1 95 100
89. González Della Valle A., Khakharia S., Glueck C. J., et al. VKORC1 variant genotypes influence warfarin response in patients undergoing total joint arthroplasty: a pilot study. Clin Orthop Relat Res: 2009; 467 7 1773 1780
90. Lazo-Langner A., Monkman K., Kovacs M. J. Predicting warfarin maintenance dose in patients with venous thromboembolism based on the response to a standardized warfarin initiation nomogram. J Thromb Haemost: 2009; 7 8 1276 1283
91. Marin-Leblanc M., Perreault S., Bahroun I., et al. Validation of warfarin pharmacogenetic algorithms in clinical practice. Pharmacogenomics: 2012; 13 1 21 29
92. Roper N., Storer B., Bona R., Fang M. Validation and comparison of pharmacogenetics-based warfarin dosing algorithms for application of pharmacogenetic testing. J Mol Diagn: 2010; 12 3 283 291
93. Sasaki T., Tabuchi H., Higuchi S., Ieiri I. Warfarin-dosing algorithm based on a population pharmacokinetic/pharmacodynamic model combined with Bayesian forecasting. Pharmacogenomics: 2009; 10 8 1257 1266
94. Schwarz U. I., Ritchie M. D., Bradford Y., et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med: 2008; 358 10 999 1008 (Pubitemid 351347099)
95. Shaw P. B., Donovan J. L., Tran M. T., Lemon S. C., Burgwinkle P., Gore J. Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic. J Thromb Thrombolysis: 2010; 30 2 220 225
96. Wells P. S., Majeed H., Kassem S., et al. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism. Thromb Res: 2010; 125 6 e259 e264
97. 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 3 460 470 (Pubitemid 351272635)
98. Eriksson N., Wadelius M. Prediction of warfarin dose: why, when and how? Pharmacogenomics: 2012; 13 4 429 440
99. Lenzini P. A., Grice G. R., Milligan P. E., et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost: 2008; 6 10 1655 1662
100. Millican E. A., Lenzini P. A., Milligan P. E., et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood: 2007; 110 5 1511 1515 (Pubitemid 47443966)
101. Voora D., McLeod H. L., Eby C., Gage B. F. The pharmacogenetics of coumarin therapy. Pharmacogenomics: 2005; 6 5 503 513 (Pubitemid 41057388)
102. Wen M. S., Lee M., Chen J. J., et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther: 2008; 84 1 83 89 (Pubitemid 351861488)
103. Connolly S. J., Pogue J., Eikelboom J., et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation: 2008; 118 20 2029 2037
104. Horne B. D., Lenzini P. A., Wadelius M., et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost: 2012; 107 2 232 240
105. Burmester J. K., Berg R. L., Yale S. H., et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med: 2011; 13 6 509 518
106. McMillin G. A., Melis R., Wilson A., et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit: 2010; 32 3 338 345
107. Carlquist J. F., Anderson J. L. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation: 2011; 124 23 2554 2559
108. Limdi N. A., Wiener H., Goldstein J. A., Acton R. T., Beasley T. M. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis: 2009; 43 1 119 128
109. Schelleman H., Limdi N. A., Kimmel S. E. Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics. Pharmacogenomics: 2008; 9 9 1331 1346
110. Yang L., Ge W., Yu F., Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirementa systematic review and meta analysis. Thromb Res: 2010; 125 4 e159 e166
111. Campbell M. C., Tishkoff S. A. African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu Rev Genomics Hum Genet: 2008; 9 403 433
112. Ramirez A. H., Shi Y., Schildcrout J. S., et al. Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenomics: 2012; 13 4 407 418
113. Limdi N. A., McGwin G., Goldstein J. A., 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 2 312 321
114. Momary K. M., Shapiro N. L., Viana M. A., Nutescu E. A., Helgason C. M., Cavallari L. H. Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics: 2007; 8 11 1535 1544 (Pubitemid 350286397)
115. Limdi N. A., Beasley T. M., Crowley M. R., et al. VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics: 2008; 9 10 1445 1458
116. Shrif N. E., Won H. H., Lee S. T., et al. Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients. Eur J Clin Pharmacol: 2011; 67 11 1119 1130
117. Mitchell C., Gregersen N., Krause A. Novel CYP2C9 and VKORC1 gene variants associated with warfarin dosage variability in the South African black population. Pharmacogenomics: 2011; 12 7 953 963
118. Dandara C., Lombard Z., Du Plooy I., McLellan T., Norris S. A., Ramsay M. Genetic variants in CYP (-1A2, -2C9, -2C19, -3A4 and -3A5), VKORC1 and ABCB1 genes in a black South African population: a window into diversity. Pharmacogenomics: 2011; 12 12 1663 1670
119. Aklillu E., Leong C., Loebstein R., Halkin H., Gak E. VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals. Blood: 2008; 111 7 3903 3904
120. Kimura R., Miyashita K., Kokubo Y., 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 2 181 186 (Pubitemid 46754413)
121. Miyagata Y., Nakai K., Sugiyama Y. Clinical significance of combined CYP2C9 and VKORC1 genotypes in Japanese patients requiring warfarin. Int Heart J: 2011; 52 1 44 49
122. Yu H. C., Chan T. Y., Critchley J. A., Woo K. S. Factors determining the maintenance dose of warfarin in Chinese patients. QJM: 1996; 89 2 127 135 (Pubitemid 26053126)
123. Lee M. T., Chen C. H., Chuang H. P., et al. VKORC1 haplotypes in five East-Asian populations and Indians. Pharmacogenomics: 2009; 10 10 1609 1616
124. Choi J. R., Kim J. O., Kang D. R., et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet: 2011; 56 4 290 295
125. Zeng W. T., Zheng Q. S., Huang M., et al. Genetic polymorphisms of VKORC1, CYP2C9, CYP4F2 in Bai, Tibetan Chinese. Pharmazie: 2012; 67 1 69 73
126. Ohno M., Yamamoto A., Ono A., et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol: 2009; 65 11 1097 1103
127. Gu Q., Kong Y., Schneede J., et al. VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China. Eur J Clin Pharmacol: 2010; 66 12 1217 1227
128. Huang S. W., Chen H. S., Wang X. Q., et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics: 2009; 19 3 226 234
129. Kim H. S., Lee S. S., Oh M., 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 2 103 112
130. Lee M. T., Chen C. H., Chou C. H., et al. Genetic determinants of warfarin dosing in the Han-Chinese population. Pharmacogenomics: 2009; 10 12 1905 1913
131. Liang R., Li L., Li C., et al. Impact of CYP2C93, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J Thromb Thrombolysis: 2012; 34 1 120 125
132. Miao L., Yang J., Huang C., 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 1141 (Pubitemid 350112769)
133. Wang T. L., Li H. L., Tjong W. Y., et al. Genetic factors contribute to patient-specific warfarin dose for Han Chinese. Clin Chim Acta: 2008; 396 1-2 76 79
134. Yang J., Huang C., Shen Z., Miao L. Contribution of 1173C>T polymorphism in the VKORC1 gene to warfarin dose requirements in Han Chinese patients receiving anticoagulation. Int J Clin Pharmacol Ther: 2011; 49 1 23 29
135. Yoshizawa M., Hayashi H., Tashiro Y., 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; 124 2 161 166
136. You J. H., Wong R. S., Waye M. M., et al. Warfarin dosing algorithm using clinical, demographic and pharmacogenetic data from Chinese patients. J Thromb Thrombolysis: 2011; 31 1 113 118
137. Zhang W., Zhang W. J., Zhu J., et al. Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism. Pharmacogenomics: 2012; 13 3 309 321
138. Lee S. C., Ng S. S., Oldenburg J., et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population. Clin Pharmacol Ther: 2006; 79 3 197 205
139. Sangviroon A., Panomvana D., Tassaneeyakul W., Namchaisiri J. Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. Drug Metab Pharmacokinet: 2010; 25 6 531 538
140. Zhao F., Loke C., Rankin S. C., et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther: 2004; 76 3 210 219 (Pubitemid 39221795)
141. Pavani A., Naushad S. M., Rupasree Y., et al. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenomics J: 2012; 12 4 306 311
142. Rathore S. S., Agarwal S. K., Pande S., Mittal T., Mittal B. Frequencies of VKORC1 -1639 G>A, CYP2C92 and CYP2C93 genetic variants in the Northern Indian population. Biosci Trends: 2010; 4 6 333 337
143. Suriapranata I. M., Tjong W. Y., Wang T., et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians. BMC Med Genet: 2011; 12 80
144. Teh L. K., Langmia I. M., Fazleen Haslinda M. H., et al. Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C93 among patients on warfarin. J Clin Pharm Ther: 2012; 37 2 232 236
145. Perini J. A., Petzl-Erler M. L., Tsuneto L. T., Suarez-Kurtz G. VKORC1 polymorphisms in Amerindian populations of Brazil. Pharmacogenomics: 2008; 9 11 1623 1629
146. Botton M. R., Bandinelli E., Rohde L. E., Amon L. C., Hutz M. H. Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry. Br J Clin Pharmacol: 2011; 72 3 442 450
147. Scibona P., Redal M. A., Garfi L. G., Arbelbide J., Argibay P. F., Belloso W. H. Prevalence of CYP2C9 and VKORC1 alleles in the Argentine population and implications for prescribing dosages of anticoagulants. Genet Mol Res: 2012; 11 1 70 76
148. Cavallari L. H., Momary K. M., Patel S. R., Shapiro N. L., Nutescu E., Viana M. A. Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells Mol Dis: 2011; 46 2 147 150
149. Palacio L., Falla D., Tobon I., et al. Pharmacogenetic impact of VKORC1 and CYP2C9 allelic variants on warfarin dose requirements in a Hispanic population isolate. Clin Appl Thromb Hemost: 2010; 16 1 83 90
150. Valentin I. I., Vazquez J., Rivera-Miranda G., et al. Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. Ann Pharmacother: 2012; 46 2 208 218
151. Villagra D., Duconge J., Windemuth A., et al. CYP2C9 and VKORC1 genotypes in Puerto Ricans: a case for admixture-matching in clinical pharmacogenetic studies. Clin Chim Acta: 2010; 411 17-18 1306 1311
152. Oner Ozgon G., Langaee T. Y., Feng H., et al. VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol: 2008; 64 9 889 894
153. Ozer N., Cam N., Tangurek B., et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population. Heart Vessels: 2010; 25 2 155 162
154. Djaffar-Jureidini I., Chamseddine N., Keleshian S., Naoufal R., Zahed L., Hakime N. Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population. Genet Test Mol Biomarkers: 2011; 15 11 827 830
155. Esmerian M. O., Mitri Z., Habbal M. Z., et al. Influence of CYP2C9 and VKORC1 polymorphisms on warfarin and acenocoumarol in a sample of Lebanese people. J Clin Pharmacol: 2011; 51 10 1418 1428
156. Pathare A. V., Al Zadjali S., Misquith R., et al. Warfarin pharmacogenetics: polymorphisms of the CYP2C9, CYP4F2, and VKORC1 loci in a genetically admixed Omani population. Hum Biol: 2012; 84 1 67 77
157. El Din M. S., Amin D. G., Ragab S. B., Ashour E. E., Mohamed M. H., Mohamed A. M. Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen. Int J Lab Hematol: 2012; 34 5 517 524
158. Shahin M. H., Khalifa S. I., Gong Y., et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics: 2011; 21 3 130 135
159. Scott S. A., Edelmann L., Kornreich R., Desnick R. J. Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations. Am J Hum Genet: 2008; 82 2 495 500
160. Cha P. C., Mushiroda T., Takahashi A., et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet: 2010; 19 23 4735 4744
161. Jorgensen A. L., Al-Zubiedi S., Zhang J. E., et al. Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics: 2009; 19 10 800 812
162. Lango A H., Estrada K., Lettre G., et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature: 2010; 467 7317 832 838
163. Cardon L. R., Palmer L. J. Population stratification and spurious allelic association. Lancet: 2003; 361 9357 598 604 (Pubitemid 36207482)
164. Marchini J., Cardon L. R., Phillips M. S., Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet: 2004; 36 5 512 517 (Pubitemid 38620038)
165. Bloss C. S., Darst B. F., Topol E. J., Schork N. J. Direct-to-consumer personalized genomic testing. Hum Mol Genet: 2011; 20 R2 R132 R141
166. Carlquist J. F., McKinney J. T., Nicholas Z. P., et al. Rapid melting curve analysis for genetic variants that underlie inter-individual variability in stable warfarin dosing. J Thromb Thrombolysis: 2008; 26 1 1 7
167. Patrick A. R., Avorn J., Choudhry N. K. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes: 2009; 2 5 429 436
168. Teichert M., Eijgelsheim M., Rivadeneira F., et al. A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet: 2009; 18 19 3758 3768