Dosing anticoagulant therapy with coumarin drugs: is genotyping clinically useful? Yes
2008; Elsevier BV; Volume: 6; Issue: 9 Linguagem: Inglês
10.1111/j.1538-7836.2008.03074.x
ISSN1538-7933
AutoresS.M. THACKER, Gloria R. Grice, Paul E. Milligan, Brian F. Gage,
Tópico(s)Hormonal Regulation and Hypertension
ResumoRecent studies have confirmed that single nucleotide polymorphisms (SNPs) in cytochrome P450 2C9 (CYP2C9) affect warfarin half‐life [1Wen M.S. Lee M. Chen J.J. Chuang H.P. Lu L.S. Chen C.H. Lee T.H. Kuo C.T. Sun F.M. Chang Y.J. Kuan P.L. Chen Y.F. Charng M.J. Ray C.Y. Wu J.Y. Chen Y.T. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes.Clin Pharmacol Ther. 2008; 84: 83-9Crossref PubMed Scopus (0) Google Scholar, 2Daly A.K. King B.P. Contribution of CYP2C9 to variability in vitamin K antagonist metabolism.Expert Opin Drug Metab Toxicol. 2006; 2: 3-15Crossref PubMed Scopus (14) Google Scholar, 3Herman D. Locatelli I. Grabnar I. Peternel P. Stegnar M. Mrhar A. Breskvar K. Dolzan V. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.Pharmacogenomics J. 2005; 5: 193-202Crossref PubMed Scopus (0) Google Scholar, 4Daly A.K. Day C.P. Aithal G.P. CYP2C9 polymorphism and warfarin dose requirements.Br J Clin Pharmacol. 2002; 53: 408-9Crossref PubMed Scopus (0) Google Scholar, 5Freeman B.D. Zehnbauer B.A. McGrath S. Borecki I. Buchman T.G. Cytochrome P450 polymorphisms are associated with reduced warfarin dose.Surgery. 2000; 128: 281-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Steward D.J. Haining R.L. Henne K.R. Davis G. Rushmore T.H. Trager W.F. Rettie A.E. Genetic association between sensitivity to warfarin and expression of CYP2C9*3.Pharmacogenetics. 1997; 7: 361-7Crossref PubMed Scopus (285) Google Scholar] and SNPs in the gene that codes for vitamin K epoxide reductase (VKOR) affect warfarin sensitivity [1Wen M.S. Lee M. Chen J.J. Chuang H.P. Lu L.S. Chen C.H. Lee T.H. Kuo C.T. Sun F.M. Chang Y.J. Kuan P.L. Chen Y.F. Charng M.J. Ray C.Y. Wu J.Y. Chen Y.T. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes.Clin Pharmacol Ther. 2008; 84: 83-9Crossref PubMed Scopus (0) Google Scholar, 7Schwarz U.I. Ritchie M.D. Bradford Y. Li C. Dudek S.M. Frye‐Anderson A. Kim R.B. Roden D.M. Stein C.M. Genetic determinants of response to warfarin during initial anticoagulation.N Engl J Med. 2008; 358: 999-1008Crossref PubMed Scopus (508) Google Scholar, 8Zhu Y. Shennan M. Reynolds K.K. Johnson N.A. Herrnberger M.R. Valdes Jr, R. Linder M.W. Estimation of warfarin maintenance dose based on VKORC1 (−1639 G>A) and CYP2C9 genotypes.Clin Chem. 2007; 53: 1199-205Crossref PubMed Scopus (0) Google Scholar, 9Loebstein R. Dvoskin I. Halkin H. Vecsler M. Lubetsky A. Rechavi G. Amariglio N. Cohen Y. Ken‐Dror G. Almog S. Gak E. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance.Blood. 2007; 109: 2477-80Crossref PubMed Scopus (137) Google Scholar, 10Wadelius M. Chen L.Y. Downes K. Ghori J. Hunt S. Eriksson N. Wallerman O. Melhus H. Wadelius C. Bentley D. Deloukas P. Common VKORC1 and GGCX polymorphisms associated with warfarin dose.Pharmacogenomics J. 2005; 5: 262-70Crossref PubMed Scopus (423) Google Scholar, 11Rieder M.J. Reiner A.P. Gage B.F. Nickerson D.A. Eby C.S. McLeod H.L. Blough D.K. Thummel K.E. Veenstra D.L. Rettie A.E. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.N Engl J Med. 2005; 352: 2285-93Crossref PubMed Scopus (1243) Google Scholar, 12Geisen C. Watzka M. Sittinger K. Steffens M. Daugela L. Seifried E. Muller C.R. Wienker T.F. Oldenburg J. VKORC1 haplotypes and their impact on the inter‐individual and inter‐ethnical variability of oral anticoagulation.Thromb Haemost. 2005; 94: 773-9PubMed Google Scholar]. Despite the successful completion of two recent randomized trials [13Anderson J.L. Horne B.D. Stevens S.M. Grove A.S. Barton S. Nicholas Z.P. Kahn S.F. May H.T. Samuelson K.M. Muhlestein J.B. Carlquist J.F. Randomized trial of genotype‐guided versus standard warfarin dosing in patients initiating oral anticoagulation.Circulation. 2007; 116: 2563-70Crossref PubMed Scopus (0) Google Scholar, 14Caraco 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: 460-70Crossref PubMed Scopus (0) Google Scholar], whether clinicians should genotype their patients beginning warfarin therapy remains controversial. In addition to randomized clinical trials and the availability of algorithms to assist in warfarin dose initiation and refinement [15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar], factors that should influence the decision to use pharmacogenetic‐based therapy are: prevalence of the polymorphisms, incidence and seriousness of adverse events and their association to genotype, accuracy and timeliness of genotyping, and costs associated with genetic testing [16Van Den Akker‐van Marle M.E. Gurwitz D. Detmar S.B. Enzing C.M. Hopkins M.M. Gutierrez de Mesa E. Ibarreta D. Cost‐effectiveness of pharmacogenomics in clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe.Pharmacogenomics. 2006; 7: 783-92Crossref PubMed Scopus (0) Google Scholar, 17Stallings S.C. Huse D. Finkelstein S.N. Crown W.H. Witt W.P. Maguire J. Hiller A.J. Sinskey A.J. Ginsburg G.S. A framework to evaluate the economic impact of pharmacogenomics.Pharmacogenomics. 2006; 7: 853-62Crossref PubMed Scopus (0) Google Scholar, 18Veenstra D.L. Higashi M.K. Phillips K.A. Assessing the cost‐effectiveness of pharmacogenomics.AAPS PharmSci. 2000; 2: E29Crossref PubMed Google Scholar, 19Hughes S. Hughes A. Brothers C. Spreen W. Thorborn D. PREDICT‐1 (CNA106030): the first powered, prospective trial of pharmacogenetic screening to reduce drug adverse events.Pharm Stat. 2008; 7: 121-9Crossref PubMed Scopus (0) Google Scholar]. The goal of this review is to clarify the potential benefits of pharmacogenetic testing and to provide guidance to assist clinicians until a multicentered randomized trial is completed. Warfarin and other coumarins exert their anticoagulant effect by interfering with clotting factor synthesis by inhibiting the vitamin K epoxide reductase (VKOR), an enzyme that is required for the regeneration of vitamin K. As detailed below, specific SNPs in the VKORC1 gene correlate with low VKOR expression, which can be overcome with low warfarin doses [20Harrington D.J. Underwood S. Morse C. Shearer M.J. Tuddenham E.G. Mumford A.D. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1.Thromb Haemost. 2005; 93: 23-6Crossref PubMed Scopus (0) Google Scholar]. Genetic polymorphisms of the CYP2C9 gene lead to decreased warfarin clearance and dose requirements [3Herman D. Locatelli I. Grabnar I. Peternel P. Stegnar M. Mrhar A. Breskvar K. Dolzan V. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.Pharmacogenomics J. 2005; 5: 193-202Crossref PubMed Scopus (0) Google Scholar, 21Takahashi H. Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications.Clin Pharmacokinet. 2001; 40: 587-603Crossref PubMed Google Scholar, 22Kim J.S. Nafziger A.N. Gaedigk A. Dickmann L.J. Rettie A.E. Bertino Jr, J.S. Effects of oral vitamin K on S‐ and R‐warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe.J Clin Pharmacol. 2001; 41: 715-22Crossref PubMed Scopus (32) Google Scholar, 23Linder M.W. Looney S. Adams III, J.E. Johnson N. Antonino‐Green D. Lacefield N. Bukaveckas B.L. Valdes Jr, R. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.J Thromb Thrombolysis. 2002; 14: 227-32Crossref PubMed Scopus (96) Google Scholar, 24Leung A.Y. Chow H.C. Kwong Y.L. Lie A.K. Fung A.T. Chow W.H. Yip A.S. Liang R. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients.Blood. 2001; 98: 2584-7Crossref PubMed Scopus (0) Google Scholar]. The wild‐type allele, denoted as CYP2C9*1, has normal metabolism of S‐warfarin. The most common variant, CYP2C9*2, is caused by the replacement of arginine with cysteine at exon 3 [3Herman D. Locatelli I. Grabnar I. Peternel P. Stegnar M. Mrhar A. Breskvar K. Dolzan V. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.Pharmacogenomics J. 2005; 5: 193-202Crossref PubMed Scopus (0) Google Scholar]. CYP2C9*2 results in a 30% reduction in S‐warfarin clearance and a 17% to 19% decrease in the steady‐state dose per allele [25Sanderson S. Emery J. Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin‐treated patients: a HuGEnet systematic review and meta‐analysis.Genet Med. 2005; 7: 97-104Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 26Aithal G.P. Day C.P. Kesteven P.J.L. Daly A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.Lancet. 1999; 353: 717-9Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar]. CYP2C9*3, caused by replacement of isoleucine with leucine at exon 7 [3Herman D. Locatelli I. Grabnar I. Peternel P. Stegnar M. Mrhar A. Breskvar K. Dolzan V. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.Pharmacogenomics J. 2005; 5: 193-202Crossref PubMed Scopus (0) Google Scholar], reduces clearance of S‐warfarin, resulting in a dose reduction of 33–37% per allele [15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar]. Six to ten percent of the variance in warfarin dosing can be explained by these CYP2C9 SNPs and they are associated with a delay until reaching stable warfarin dosing [27Higashi M.K. Veenstra D.L. Kondo L.M. Wittkowsky A.K. Srinouanprachanh S.L. Farin F.M. Rettie A.E. Association between CYP2C9 genetic variants and anticoagulation‐related outcomes during warfarin therapy.JAMA. 2002; 287: 1690-8Crossref PubMed Google Scholar]. The prevalence of these SNPs varies by race (Table 1). Other CYP2C9 SNPs (e.g. CYP2C9*5, CYP2C9*6, and CYP2C9*11) are rare (<1%) in Caucasian and Asian populations, but they are more common in African ancestry populations and may also reduce the warfarin dose [28Dickmann L.J. Rettie A.E. Kneller M.B. Kim R.B. Wood A.J. Stein C.M. Wilkinson G.R. Schwarz U.I. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans.Mol Pharmacol. 2001; 60: 382-7Crossref PubMed Scopus (253) Google Scholar, 29Allabi A.C. Gala J.L. Horsmans Y. Babaoglu M.O. Bozkurt A. Heusterspreute M. Yasar U. Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans.Clin Pharmacol Ther. 2004; 76: 113-8Crossref PubMed Scopus (0) Google Scholar, 30Kidd R.S. Curry T.B. Gallagher S. Edeki T. Blaisdell J. Goldstein J.A. Identification of a null allele of CYP2C9 in an African‐American exhibiting toxicity to phenytoin.Pharmacogenetics. 2001; 11: 803-8Crossref PubMed Scopus (0) Google Scholar, 31Rettie A.E. Farin F.M. Beri N.G. Srinouanprachanh S.L. Rieder M.J. Thijssen H.H. A case study of acenocoumarol sensitivity and genotype‐phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9.Br J Clin Pharmacol. 2006; 62: 617-20Crossref PubMed Scopus (0) Google Scholar, 32Tai G. Farin F. Rieder M.J. Dreisbach A.W. Veenstra D.L. Verlinde C.L. Rettie A.E. In‐vitro and in‐vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose.Pharmacogenet Genomics. 2005; 15: 475-81Crossref PubMed Google Scholar]. Additionally, variants in the CYP2C9 alleles are associated with a delay until reaching stable warfarin dosing [27Higashi M.K. Veenstra D.L. Kondo L.M. Wittkowsky A.K. Srinouanprachanh S.L. Farin F.M. Rettie A.E. Association between CYP2C9 genetic variants and anticoagulation‐related outcomes during warfarin therapy.JAMA. 2002; 287: 1690-8Crossref PubMed Google Scholar].Table 1Prevalence of Genetic Polymorphisms by RacePopulationVKORC1 A haplotypeCYP2C9*2CYP2C9*3SNPs of Special InterestReferencesAfrican‐American9–24%5%1–3%CYP2C9*5, CYP2C9*6[11Rieder M.J. Reiner A.P. Gage B.F. Nickerson D.A. Eby C.S. McLeod H.L. Blough D.K. Thummel K.E. Veenstra D.L. Rettie A.E. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.N Engl J Med. 2005; 352: 2285-93Crossref PubMed Scopus (1243) Google Scholar, 15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar, 54Marsh 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: 473-4Crossref PubMed Scopus (0) Google Scholar]Asian74–89% C [rs17886369], which denotes haplotype group A or H1, predicts lower doses in patients taking warfarin chronically [11Rieder M.J. Reiner A.P. Gage B.F. Nickerson D.A. Eby C.S. McLeod H.L. Blough D.K. Thummel K.E. Veenstra D.L. Rettie A.E. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.N Engl J Med. 2005; 352: 2285-93Crossref PubMed Scopus (1243) Google Scholar]. At least in Asian and Caucasian populations, this warfarin‐sensitive allele also correlates with a VKORC1 1173 C>T SNP that is associated with coumarin sensitivity [35Reitsma P.H. Heijden J.F. Groot A.P. Rosendaal F.R. Buller H.R. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.PLoS Med. 2005; 2: e312Crossref PubMed Scopus (0) Google Scholar]. Of several VKORC1 SNPs, −1639 G>A (originally called VKORC1 3673) appears to be the best predictor of warfarin dose, accounting for 25% of the variability in dose [15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar]. Other VKORC1 SNPs may help predict warfarin resistance [9Loebstein R. Dvoskin I. Halkin H. Vecsler M. Lubetsky A. Rechavi G. Amariglio N. Cohen Y. Ken‐Dror G. Almog S. Gak E. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance.Blood. 2007; 109: 2477-80Crossref PubMed Scopus (137) Google Scholar], but require validation before being used clinically [36Caldwell M.D. Awad T. Johnson J.A. Gage B.F. Falkowski M. Gardina P. Hubbard J. Turpaz Y. Langaee T.Y. Eby C. King C.R. Brower A. Schmelzer J.R. Glurich I. Vidaillet H.J. Yale S.H. Qi Zhang K. Berg R.L. Burmester J.K. CYP4F2 genetic variant alters required warfarin dose.Blood. 2008; 111: 4106-12Crossref PubMed Scopus (445) Google Scholar]. Together, the common VKORC1 and CYP2C9 SNPs explain 30–35% of the variability in warfarin dose [11Rieder M.J. Reiner A.P. Gage B.F. Nickerson D.A. Eby C.S. McLeod H.L. Blough D.K. Thummel K.E. Veenstra D.L. Rettie A.E. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.N Engl J Med. 2005; 352: 2285-93Crossref PubMed Scopus (1243) Google Scholar, 15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar, 33D'Andrea G. D'Ambrosio R.L. Di Perna P. Chetta M. Santacroce R. Brancaccio V. Grandone E. Margaglione M. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose‐anticoagulant effect of warfarin.Blood. 2005; 105: 645-9Crossref PubMed Scopus (0) Google Scholar]. Pharmacogenetic algorithms have been developed and validated to assist the clinician with adjusting the first few warfarin doses [37Millican E. Lenzini P. Milligan P. Grosso L. Eby C. Deych E. Grice G. Clohisy J. Barrack R. Burnett R. Voora D. Gatchel S. Tiemeier A. Gage B. Genetic‐based dosing in orthopaedic patients beginning warfarin therapy.Blood. 2007; 110: 1511-5Crossref PubMed Scopus (0) Google Scholar, 38Lenzini P. Grice G. Milligan P. Gatchel S. Deych E. Eby C. Burnett R.S. Clohisy J. Barrack R. Gage B. Optimal dose adjustment in orthopaedic patients beginning warfarin therapy.Ann Pharmacother. 2007; 41: 1798-804Crossref PubMed Scopus (0) Google Scholar, 39Lenzini P.A. Grice G.R. Milligan P.E. Dowd M.B. Subherwal S. Deych E. Eby C.S. King C.R. Porche‐Sorbet R.M. Murphy C.V. Marchand R. Millican E.A. Barrack R.L. Clohisy J.C. Kronquist K. Gatchel S.K. Gage B.F. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.J Thromb Haemost. 2008; https://doi.org/10.1111/j.1538-7836.2008.03095.xAbstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. To improve the accuracy of algorithms that predict the therapeutic warfarin dose, researchers have combined these SNPs with clinical factors, such as demographics, concomitant medications, and sometimes International Normalized Ratios (INRs), to explain approximately half of the variability in dose (Table 2). Although the coefficients of variables included in these dosing algorithms differ, the algorithms agree on important relationships. For example, predicted therapeutic doses decline with age and increase with body size.Table 2Pharmacogenetic algorithms using VKORC1 and CYP2C9 to predict the therapeutic warfarin doseReferenceCity, CountryVKORC1 SNPs in AlgorithmDerivation Samp1e (N)Derivation R2Validation[1Wen M.S. Lee M. Chen J.J. Chuang H.P. Lu L.S. Chen C.H. Lee T.H. Kuo C.T. Sun F.M. Chang Y.J. Kuan P.L. Chen Y.F. Charng M.J. Ray C.Y. Wu J.Y. Chen Y.T. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes.Clin Pharmacol Ther. 2008; 84: 83-9Crossref PubMed Scopus (0) Google Scholar]Taoyuan, Taiwan3673 G>A10862%NA[58Sconce E.A. Khan T.I. Wynne H.A. Avery P. Monkhouse L. King B.P. Wood P. Kesteven P. Daly A.K. Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.Blood. 2005; 106: 2329-33Crossref PubMed Scopus (833) Google Scholar]Newcastle upon Tyne, UK3673 G>A29754%Retrospective[59Aquilante C.L. Langaee T.Y. Lopez L.M. Yarandi H.N. Tromberg J.S. Mohuczy D. Gaston K.L. Waddell C.D. Chirico M.J. Johnson J.A. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements.Clin Pharmacol Ther. 2006; 79: 291-302Crossref PubMed Scopus (257) Google Scholar]Gainesville, US3673 G>A35051%NA[10Wadelius M. Chen L.Y. Downes K. Ghori J. Hunt S. Eriksson N. Wallerman O. Melhus H. Wadelius C. Bentley D. Deloukas P. Common VKORC1 and GGCX polymorphisms associated with warfarin dose.Pharmacogenomics J. 2005; 5: 262-70Crossref PubMed Scopus (423) Google Scholar]Uppsala, Sweden7566 C>T20156%NA[60Herman D. Peternel P. Stegnar M. Breskvar K. Dolzan V. The influence of sequence variations in factor VII, gamma‐glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement.Thromb Haemost. 2006; 95: 782-7Crossref PubMed Scopus (0) Google Scholar]Ljubljana, Slovenia6484C>T; 9041 G>A16560%NA[61Tham L.S. Goh B.C. Nafziger A. Guo J.Y. Wang L.Z. Soong R. Lee S.C. A warfarin‐dosing model in Asians that uses single‐nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9.Clin Pharmacol Ther. 2006; 80: 346-55Crossref PubMed Scopus (0) Google Scholar]Singapore381 T>C10760%Retrospective[8Zhu Y. Shennan M. Reynolds K.K. Johnson N.A. Herrnberger M.R. Valdes Jr, R. Linder M.W. Estimation of warfarin maintenance dose based on VKORC1 (−1639 G>A) and CYP2C9 genotypes.Clin Chem. 2007; 53: 1199-205Crossref PubMed Scopus (0) Google Scholar]Louisville, US3673 G>A6561%NA[62Caldwell M.D. Berg R.L. Zhang K.Q. Glurich I. Schmelzer J.R. Yale S.H. Vidaillet H.J. Burmester J.K. Evaluation of genetic factors for warfarin dose prediction.Clin Med Res. 2007; 5: 8-16Crossref PubMed Scopus (0) Google Scholar]Marshfield, US6853 G>C57056%Retrospective[37Millican E. Lenzini P. Milligan P. Grosso L. Eby C. Deych E. Grice G. Clohisy J. Barrack R. Burnett R. Voora D. Gatchel S. Tiemeier A. Gage B. Genetic‐based dosing in orthopaedic patients beginning warfarin therapy.Blood. 2007; 110: 1511-5Crossref PubMed Scopus (0) Google Scholar]St. Louis, US3673 G>A9279%NA[52Carlquist J.F. Horne B.D. Muhlestein J.B. Lappe D.L. Whiting B.M. Kolek M.J. Clarke J.L. James B.C. Anderson J.L. 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: 191-7Crossref PubMed Scopus (0) Google Scholar]Salt Lake City, US1173 C>T21345%NA[63Sakamoto T. Kojima S. Ogawa H. Shimomura H. Kimura K. Ogata Y. Sakaino N. Kitagawa A. Usefulness of hydrophilic vs. lipophilic statins after acute myocardial infarction: subanalysis of MUSASHI‐AMI.Circ J. 2007; 71: 1348-53Crossref PubMed Scopus (0) Google Scholar]Osaka, Japan3673 G>A; 9041 G>A9333%NA[13Anderson J.L. Horne B.D. Stevens S.M. Grove A.S. Barton S. Nicholas Z.P. Kahn S.F. May H.T. Samuelson K.M. Muhlestein J.B. Carlquist J.F. Randomized trial of genotype‐guided versus standard warfarin dosing in patients initiating oral anticoagulation.Circulation. 2007; 116: 2563-70Crossref PubMed Scopus (0) Google Scholar]Salt Lake City, US1173 C>T20047%Randomized[64Wu A.H. Wang P. Smith A. Haller C. Drake K. Linder M. Valdes R. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi‐ethnic population: comparison with other equations.Pharmacogenomics. 2008; 9: 169-78Crossref PubMed Scopus (0) Google Scholar]San Francisco and Louisville, US3673 G>A; 7566 C>T9250%Retrospective[65Gage B.F. Yan Y. Milligan P.E. Waterman A.D. Culverhouse R. Rich M.W. Radford M.J. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).Am Heart J. 2006; 151: 713-9Crossref PubMed Scopus (805) Google Scholar]Multicentered, US3673 G>A101554%Prospective[39Lenzini P.A. Grice G.R. Milligan P.E. Dowd M.B. Subherwal S. Deych E. Eby C.S. King C.R. Porche‐Sorbet R.M. Murphy C.V. Marchand R. Millican E.A. Barrack R.L. Clohisy J.C. Kronquist K. Gatchel S.K. Gage B.F. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.J Thromb Haemost. 2008; https://doi.org/10.1111/j.1538-7836.2008.03095.xAbstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]St. Louis and Denver, US3673 G>A8682%ProspectiveNA, not applicable; SNP, single nucleotide polymorphism; VKORC1,Vitamin K epoxide reductase gene; RCT, randomized, controlled trial; N, sample size. The VKORC13673 G>A SNP is more recently referred to as VKORC1‐1639 G>A [34Yuan H.Y. Chen J.J. Lee M.T. Wung J.C. Chen Y.F. Charng M.J. Lu M.J. Hung C.R. Wei C.Y. Chen C.H. Wu J.Y. Chen Y.T. A novel functional VKORC1 promoter polymorphism is associated with inter‐individual and inter‐ethnic differences in warfarin sensitivity.Hum Mol Genet. 2005; 14: 1745-51Crossref PubMed Scopus (0) Google Scholar]. Open table in a new tab NA, not applicable; SNP, single nucleotide polymorphism; VKORC1,Vitamin K epoxide reductase gene; RCT, randomized, controlled trial; N, sample size. The VKORC13673 G>A SNP is more recently referred to as VKORC1‐1639 G>A [34Yuan H.Y. Chen J.J. Lee M.T. Wung J.C. Chen Y.F. Charng M.J. Lu M.J. Hung C.R. Wei C.Y. Chen C.H. Wu J.Y. Chen Y.T. A novel functional VKORC1 promoter polymorphism is associated with inter‐individual and inter‐ethnic differences in warfarin sensitivity.Hum Mol Genet. 2005; 14: 1745-51Crossref PubMed Scopus (0) Google Scholar]. Clinicians using these algorithms should understand their limitations. First, few algorithms have been validated prospectively (Table 2). Secondly, none of them is accurate enough to replace INR monitoring. Thirdly, they estimate a therapeutic dose, but to minimize the delay until the INR is therapeutic, clinicians may prefer to prescribe a larger first or second dose [13Anderson J.L. Horne B.D. Stevens S.M. Grove A.S. Barton S. Nicholas Z.P. Kahn S.F. May H.T. Samuelson K.M. Muhlestein J.B. Carlquist J.F. Randomized trial of genotype‐guided versus standard warfarin dosing in patients initiating oral anticoagulation.Circulation. 2007; 116: 2563-70Crossref PubMed Scopus (0) Google Scholar, 40Kovacs M.J. Cruickshank M. Wells P.S. Kim H. Chin‐Yee I. Morrow B. Boyle E. Kovacs J. Randomized assessment of a warfarin nomogram for initial oral anticoagulation after venous thromboembolic disease.Haemostasis. 1998; 28: 62-9PubMed Google Scholar]. A small loading dose may be most helpful in poor metabolizers [15Gage B. Eby C. Johnson J. Deych E. Rieder M. Ridker P. Milligan P. Grice G. Lenzini P. Rettie A. Aquilante C. Grosso L. Marsh S. Langaee T. Farnett L. Voora D. Veenstra D. Glynn R. Barrett A. McLeod H. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.Clin Pharmacol Ther. 2008; Crossref PubMed Scopus (678) Google Scholar] who otherwise would remain subtherapeutic for more than a week [23Linder M.W. Looney S. Adams III, J.E. Johnson N. Antonino‐Green D. Lacefield N. Bukaveckas B.L. Valdes Jr, R. Warfarin dose adjus
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