Download PDF
Semin Thromb Hemost 2012; 38(08): 893-904
DOI: 10.1055/s-0032-1328891
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

Erik Fung
1   Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
2   Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
,
Nikolaos A. Patsopoulos
3   Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
4   Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
5   Broad Institute of Harvard and MIT, Cambridge, Massachusetts
,
Steven M. Belknap
6   Department of Medicine, Northwestern Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois
,
Daniel J. O'Rourke
1   Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
2   Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
7   Section of Cardiology, Veterans Affairs Medical Center, White River Junction, Vermont
,
John F. Robb
1   Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
2   Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
,
Jeffrey L. Anderson
8   Cardiovascular Department, Intermountain Medical Center, Murray, Utah
9   University of Utah School of Medicine, Salt Lake City, Utah
,
Nicholas W. Shworak
1   Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
2   Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
10   Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
,
Jason H. Moore
2   Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
11   Institute of Quantitative Biomedical Science, Dartmouth College, Hanover, New Hampshire
12   Departments of Genetics and Community and Family Medicine, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire
› Author Affiliations
Further Information

Publication History

Publication Date:
06 October 2012 (online)

    Permissions and Reprints

Corrected by:

Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of WarfarinSemin Thromb Hemost 2013; 39(01): 112-112
DOI: 10.1055/s-0032-1333535

Abstract

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways.

Keywords

warfarin - pharmacogenetics - polymorphisms - personalized medicine
 

  • References

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 2 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12) 857-867
    CrossrefPubMedSearch in Google Scholar
  • 3 Petersen P, Boysen G, Godtfredsen J, Andersen ED, 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
    PubMedSearch in Google Scholar
  • 4 Avorn J. The relative cost-effectiveness of anticoagulants: obvious, except for the cost and the effectiveness. Circulation 2011; 123 (22) 2519-2521
    CrossrefPubMedSearch in Google Scholar
  • 5 Friberg L, Rosenqvist M, Lip GY. 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
    CrossrefPubMedSearch in Google Scholar
  • 6 Flockhart DA, O'Kane D, Williams MS , et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med 2008; 10 (2) 139-150
    CrossrefPubMedSearch in Google Scholar
  • 7 Wysowski DK, 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
    CrossrefPubMedSearch in Google Scholar
  • 8 Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000; 160 (11) 1612-1617
    CrossrefPubMedSearch in Google Scholar
  • 9 Merli GJ, 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Oake N, Jennings A, Forster AJ, 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
    CrossrefPubMedSearch in Google Scholar
  • 11 Cooper GM, Johnson JA, Langaee TY , et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008; 112 (4) 1022-1027
    CrossrefPubMedSearch in Google Scholar
  • 12 Kamali F, Wynne H. Pharmacogenetics of warfarin. Annu Rev Med 2010; 61: 63-75
    CrossrefPubMedSearch in Google Scholar
  • 13 Skov J, Bladbjerg EM, Rasmussen MA, Sidelmann JJ, 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 16 Anderson JL, Horne BD, Stevens SM , et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116 (22) 2563-2570
    CrossrefPubMedSearch in Google Scholar
  • 17 Anderson JL, Horne BD, Stevens SM , 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
    CrossrefPubMedSearch in Google Scholar
  • 18 Gong IY, Tirona RG, Schwarz UI , et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 2011; 118 (11) 3163-3171
    CrossrefPubMedSearch in Google Scholar
  • 19 Epstein RS, Moyer TP, Aubert RE , 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Klein TE, Altman RB, 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
    CrossrefPubMedSearch in Google Scholar
  • 21 Rieder MJ, Reiner AP, Gage BF , et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352 (22) 2285-2293
    CrossrefPubMedSearch in Google Scholar
  • 22 Sconce EA, Khan TI, Wynne HA , 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
    CrossrefPubMedSearch in Google Scholar
  • 23 Lam MP, Cheung BM. The pharmacogenetics of the response to warfarin in Chinese. Br J Clin Pharmacol 2012; 73 (3) 340-347
    CrossrefPubMedSearch in Google Scholar
  • 24 Limdi NA, 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
    CrossrefPubMedSearch in Google Scholar
  • 25 Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ. CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics 2009; 10 (8) 1243-1255
    CrossrefPubMedSearch in Google Scholar
  • 26 Wadelius M, Chen LY, Lindh JD , et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113 (4) 784-792
    CrossrefPubMedSearch in Google Scholar
  • 27 Chan SL, Suo C, Lee SC , 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
    PubMedSearch in Google Scholar
  • 28 Shuen AY, Wong BY, Fu L, Selby R, Cole DE. 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
    CrossrefPubMedSearch in Google Scholar
  • 29 Poller L. International Normalized Ratios (INR): the first 20 years. J Thromb Haemost 2004; 2 (6) 849-860
    CrossrefPubMedSearch in Google Scholar
  • 30 Kirkwood TB. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Thromb Haemost 1983; 49 (3) 238-244
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 32 Crowther MA, Harrison L, Hirsh J. Randomized trial of warfarin nomograms. Ann Intern Med 2004; 140 (6) 490 , author reply 491–492
    PubMedSearch in Google Scholar
  • 33 Kovacs MJ, Rodger M, Anderson DR , 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
    CrossrefPubMedSearch in Google Scholar
  • 34 Roberts GW, Druskeit T, Jorgensen LE , 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
    CrossrefPubMedSearch in Google Scholar
  • 35 Tait RC, Sefcick A. A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation. Br J Haematol 1998; 101 (3) 450-454
    CrossrefPubMedSearch in Google Scholar
  • 36 Li-Saw-Hee FL, Blann AD, Lip GY. 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
    CrossrefPubMedSearch in Google Scholar
  • 37 Holbrook AM, Pereira JA, Labiris R , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
    CrossrefPubMedSearch in Google Scholar
  • 38 Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother 2005; 39 (6) 1008-1012
    CrossrefPubMedSearch in Google Scholar
  • 39 Gurwitz JH, 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
    CrossrefPubMedSearch in Google Scholar
  • 40 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 (2) 89-98
    CrossrefPubMedSearch in Google Scholar
  • 41 Wynne HA, 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
    CrossrefPubMedSearch in Google Scholar
  • 42 Gage BF, Eby C, Johnson JA , et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84 (3) 326-331
    CrossrefPubMedSearch in Google Scholar
  • 43 Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009; 30 (7) 375-386
    CrossrefPubMedSearch in Google Scholar
  • 44 Burmester JK, Berg RL, Glurich I, Yale SH, Schmelzer JR, Caldwell MD. 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
    PubMedSearch in Google Scholar
  • 45 Scott SA, 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
    CrossrefPubMedSearch in Google Scholar
  • 46 Moyer TP, O'Kane DJ, Baudhuin LM , et al. Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Mayo Clin Proc 2009; 84 (12) 1079-1094
    CrossrefPubMedSearch in Google Scholar
  • 47 Rettie AE, Korzekwa KR, Kunze KL , 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
    CrossrefPubMedSearch in Google Scholar
  • 48 Rettie AE, Jones JP. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol 2005; 45: 477-494
    CrossrefPubMedSearch in Google Scholar
  • 49 de Morais SM, Schweikl H, Blaisdell J, Goldstein JA. Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18. Biochem Biophys Res Commun 1993; 194 (1) 194-201
    CrossrefPubMedSearch in Google Scholar
  • 50 Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6 (5) 429-439
    CrossrefPubMedSearch in Google Scholar
  • 51 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 (2) 447-458
    CrossrefPubMedSearch in Google Scholar
  • 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 (1) 39-42
    CrossrefPubMedSearch in Google Scholar
  • 53 Margaglione M, Colaizzo D, D'Andrea G , et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84 (5) 775-778
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 55 Linder MW, Bon Homme M, Reynolds KK , et al. Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy. Clin Chem 2009; 55 (10) 1861-1868
    CrossrefPubMedSearch in Google Scholar
  • 56 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 (9154) 717-719
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 58 Higashi MK, Veenstra DL, Kondo LM , et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287 (13) 1690-1698
    CrossrefPubMedSearch in Google Scholar
  • 59 Hillman MA, Wilke RA, Caldwell MD, Berg RL, Glurich I, Burmester JK. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 2004; 14 (8) 539-547
    CrossrefPubMedSearch in Google Scholar
  • 60 Steward DJ, Haining RL, Henne KR , et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 7 (5) 361-367
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 62 Cavallari LH, Langaee TY, Momary KM , et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 2010; 87 (4) 459-464
    CrossrefPubMedSearch in Google Scholar
  • 63 Dickmann LJ, Rettie AE, Kneller MB , et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 2001; 60 (2) 382-387
    PubMedSearch in Google Scholar
  • 64 Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics 2010; 11 (6) 781-791
    CrossrefPubMedSearch in Google Scholar
  • 65 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 (3) 1085-1090
    CrossrefPubMedSearch in Google Scholar
  • 66 Oldenburg J, Marinova M, Müller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm 2008; 78: 35-62
    PubMedSearch in Google Scholar
  • 67 Rasmussen MA, Skov J, Bladbjerg EM, Sidelmann JJ, Vamosi M, Jespersen J. Multivariate analysis of the relation between diet and warfarin dose. Eur J Clin Pharmacol 2012; 68 (3) 321-328
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 69 Stafford DW. The vitamin K cycle. J Thromb Haemost 2005; 3 (8) 1873-1878
    CrossrefPubMedSearch in Google Scholar
  • 70 Oldenburg J, Watzka M, Rost S, Müller CR. VKORC1: molecular target of coumarins. J Thromb Haemost 2007; 5 (Suppl. 01) 1-6
    PubMedSearch in Google Scholar
  • 71 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 (4) 1013-1021
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 73 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427 (6974) 541-544
    CrossrefPubMedSearch in Google Scholar
  • 74 Harrington DJ, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 76 D'Andrea G, D'Ambrosio RL, 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
    CrossrefPubMedSearch in Google Scholar
  • 77 Loebstein R, Dvoskin I, Halkin H , et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109 (6) 2477-2480
    CrossrefPubMedSearch in Google Scholar
  • 78 Marsh S, King CR, Porche-Sorbet RM, Scott-Horton TJ, Eby CS. Population variation in VKORC1 haplotype structure. J Thromb Haemost 2006; 4 (2) 473-474
    CrossrefPubMedSearch in Google Scholar
  • 79 Watzka M, Geisen C, Bevans CG , 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
    CrossrefPubMedSearch in Google Scholar
  • 80 Aquilante CL, Langaee TY, Lopez LM , 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
    CrossrefPubMedSearch in Google Scholar
  • 81 Carlquist JF, Horne BD, Muhlestein JB , 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 84 Wadelius M, Chen LY, Downes K , et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5 (4) 262-270
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 86 Cho HJ, On YK, Bang OY , et al. Development and comparison of a warfarin-dosing algorithm for Korean patients with atrial fibrillation. Clin Ther 2011; 33 (10) 1371-1380
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 88 Ferder NS, Eby CS, 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
    CrossrefPubMedSearch in Google Scholar
  • 89 González Della Valle A, Khakharia S, Glueck CJ , 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
    CrossrefPubMedSearch in Google Scholar
  • 90 Lazo-Langner A, Monkman K, Kovacs MJ. 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
    CrossrefPubMedSearch in Google Scholar
  • 91 Marin-Leblanc M, Perreault S, Bahroun I , et al. Validation of warfarin pharmacogenetic algorithms in clinical practice. Pharmacogenomics 2012; 13 (1) 21-29
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 94 Schwarz UI, Ritchie MD, Bradford Y , et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358 (10) 999-1008
    CrossrefPubMedSearch in Google Scholar
  • 95 Shaw PB, Donovan JL, Tran MT, Lemon SC, 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
    CrossrefPubMedSearch in Google Scholar
  • 96 Wells PS, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 98 Eriksson N, Wadelius M. Prediction of warfarin dose: why, when and how?. Pharmacogenomics 2012; 13 (4) 429-440
    CrossrefPubMedSearch in Google Scholar
  • 99 Lenzini PA, Grice GR, Milligan PE , 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
    CrossrefPubMedSearch in Google Scholar
  • 100 Millican EA, Lenzini PA, Milligan PE , et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 2007; 110 (5) 1511-1515
    CrossrefPubMedSearch in Google Scholar
  • 101 Voora D, McLeod HL, Eby C, Gage BF. The pharmacogenetics of coumarin therapy. Pharmacogenomics 2005; 6 (5) 503-513
    CrossrefPubMedSearch in Google Scholar
  • 102 Wen MS, Lee M, Chen JJ , et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther 2008; 84 (1) 83-89
    CrossrefPubMedSearch in Google Scholar
  • 103 Connolly SJ, 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
    CrossrefPubMedSearch in Google Scholar
  • 104 Horne BD, Lenzini PA, 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
    PubMedSearch in Google Scholar
  • 105 Burmester JK, Berg RL, Yale SH , et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med 2011; 13 (6) 509-518
    CrossrefPubMedSearch in Google Scholar
  • 106 McMillin GA, 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
    CrossrefPubMedSearch in Google Scholar
  • 107 Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 2011; 124 (23) 2554-2559
    CrossrefPubMedSearch in Google Scholar
  • 108 Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 2009; 43 (1) 119-128
    CrossrefPubMedSearch in Google Scholar
  • 109 Schelleman H, Limdi NA, Kimmel SE. Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics. Pharmacogenomics 2008; 9 (9) 1331-1346
    CrossrefPubMedSearch in Google Scholar
  • 110 Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement—a systematic review and meta analysis. Thromb Res 2010; 125 (4) e159-e166
    CrossrefPubMedSearch in Google Scholar
  • 111 Campbell MC, Tishkoff SA. African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu Rev Genomics Hum Genet 2008; 9: 403-433
    CrossrefPubMedSearch in Google Scholar
  • 112 Ramirez AH, Shi Y, Schildcrout JS , 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
    CrossrefPubMedSearch in Google Scholar
  • 113 Limdi NA, McGwin G, Goldstein JA , 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
    CrossrefPubMedSearch in Google Scholar
  • 114 Momary KM, Shapiro NL, Viana MA, Nutescu EA, Helgason CM, Cavallari LH. Factors influencing warfarin dose requirements in African-Americans. Pharmacogenomics 2007; 8 (11) 1535-1544
    CrossrefPubMedSearch in Google Scholar
  • 115 Limdi NA, Beasley TM, Crowley MR , et al. VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics 2008; 9 (10) 1445-1458
    CrossrefPubMedSearch in Google Scholar
  • 116 Shrif NE, Won HH, Lee ST , 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 118 Dandara C, Lombard Z, Du Plooy I, McLellan T, Norris SA, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 122 Yu HC, Chan TY, Critchley JA, Woo KS. Factors determining the maintenance dose of warfarin in Chinese patients. QJM 1996; 89 (2) 127-135
    CrossrefPubMedSearch in Google Scholar
  • 123 Lee MT, Chen CH, Chuang HP , et al. VKORC1 haplotypes in five East-Asian populations and Indians. Pharmacogenomics 2009; 10 (10) 1609-1616
    CrossrefPubMedSearch in Google Scholar
  • 124 Choi JR, Kim JO, Kang DR , et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet 2011; 56 (4) 290-295
    CrossrefPubMedSearch in Google Scholar
  • 125 Zeng WT, Zheng QS, Huang M , et al. Genetic polymorphisms of VKORC1, CYP2C9, CYP4F2 in Bai, Tibetan Chinese. Pharmazie 2012; 67 (1) 69-73
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 128 Huang SW, Chen HS, Wang XQ , 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
    CrossrefPubMedSearch in Google Scholar
  • 129 Kim HS, Lee SS, 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
    CrossrefPubMedSearch in Google Scholar
  • 130 Lee MT, Chen CH, Chou CH , et al. Genetic determinants of warfarin dosing in the Han-Chinese population. Pharmacogenomics 2009; 10 (12) 1905-1913
    CrossrefPubMedSearch in Google Scholar
  • 131 Liang R, Li L, Li C , et al. Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J Thromb Thrombolysis 2012; 34 (1) 120-125
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 133 Wang TL, Li HL, Tjong WY , et al. Genetic factors contribute to patient-specific warfarin dose for Han Chinese. Clin Chim Acta 2008; 396 (1–2) 76-79
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 136 You JH, Wong RS, Waye MM , et al. Warfarin dosing algorithm using clinical, demographic and pharmacogenetic data from Chinese patients. J Thromb Thrombolysis 2011; 31 (1) 113-118
    CrossrefPubMedSearch in Google Scholar
  • 137 Zhang W, Zhang WJ, 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
    CrossrefPubMedSearch in Google Scholar
  • 138 Lee SC, Ng SS, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 140 Zhao F, Loke C, Rankin SC , et al. Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther 2004; 76 (3) 210-219
    CrossrefPubMedSearch in Google Scholar
  • 141 Pavani A, Naushad SM, Rupasree Y , et al. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenomics J 2012; 12 (4) 306-311
    CrossrefPubMedSearch in Google Scholar
  • 142 Rathore SS, Agarwal SK, Pande S, Mittal T, Mittal B. Frequencies of VKORC1 -1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population. Biosci Trends 2010; 4 (6) 333-337
    PubMedSearch in Google Scholar
  • 143 Suriapranata IM, Tjong WY, Wang T , et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians. BMC Med Genet 2011; 12: 80
    PubMedSearch in Google Scholar
  • 144 Teh LK, Langmia IM, Fazleen Haslinda MH , et al. Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. J Clin Pharm Ther 2012; 37 (2) 232-236
    CrossrefPubMedSearch in Google Scholar
  • 145 Perini JA, Petzl-Erler ML, Tsuneto LT, Suarez-Kurtz G. VKORC1 polymorphisms in Amerindian populations of Brazil. Pharmacogenomics 2008; 9 (11) 1623-1629
    CrossrefPubMedSearch in Google Scholar
  • 146 Botton MR, Bandinelli E, Rohde LE, Amon LC, Hutz MH. 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
    CrossrefPubMedSearch in Google Scholar
  • 147 Scibona P, Redal MA, Garfi LG, Arbelbide J, Argibay PF, Belloso WH. 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
    CrossrefPubMedSearch in Google Scholar
  • 148 Cavallari LH, Momary KM, Patel SR, Shapiro NL, Nutescu E, Viana MA. Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells Mol Dis 2011; 46 (2) 147-150
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 150 Valentin II, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 152 Oner Ozgon G, Langaee TY, 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 155 Esmerian MO, Mitri Z, Habbal MZ , 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
    CrossrefPubMedSearch in Google Scholar
  • 156 Pathare AV, 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
    CrossrefPubMedSearch in Google Scholar
  • 157 El Din MS, Amin DG, Ragab SB, Ashour EE, Mohamed MH, Mohamed AM. 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
    CrossrefPubMedSearch in Google Scholar
  • 158 Shahin MH, Khalifa SI, Gong Y , et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics 2011; 21 (3) 130-135
    CrossrefPubMedSearch in Google Scholar
  • 159 Scott SA, Edelmann L, Kornreich R, Desnick RJ. 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
    CrossrefPubMedSearch in Google Scholar
  • 160 Cha PC, 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
    CrossrefPubMedSearch in Google Scholar
  • 161 Jorgensen AL, Al-Zubiedi S, Zhang JE , et al. Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics 2009; 19 (10) 800-812
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 163 Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 2003; 361 (9357) 598-604
    CrossrefPubMedSearch in Google Scholar
  • 164 Marchini J, Cardon LR, Phillips MS, Donnelly P. The effects of human population structure on large genetic association studies. Nat Genet 2004; 36 (5) 512-517
    CrossrefPubMedSearch in Google Scholar
  • 165 Bloss CS, Darst BF, Topol EJ, Schork NJ. Direct-to-consumer personalized genomic testing. Hum Mol Genet 2011; 20 (R2) R132-R141
    CrossrefPubMedSearch in Google Scholar
  • 166 Carlquist JF, McKinney JT, Nicholas ZP , 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
    CrossrefPubMedSearch in Google Scholar
  • 167 Patrick AR, Avorn J, Choudhry NK. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009; 2 (5) 429-436
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar