Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes

Wen, Ming‐Shien; Lee, M. T. M; Chen, J.-J.; Chuang, Hui-Ping; Lu, Limin; Chen, C.-H.; Lee, T.-H.; Kuo, Chiu‐Huang; Sun, Feng; Chang, Yeu-Jhy; Kuan, P.-L.; Chen, Y.-F.; Charng, Min‐Ji; Ray, CK; Wu, Jer‐Yuarn; Chen, Y.-T.

doi:10.1038/sj.clpt.6100453

Cited by 131 publications

(109 citation statements)

References 42 publications

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“…White people show considerable variability in CYP2C9, whereas people of African and Asian descent are predominantly of the CYP2C9*1*1 genotype, predisposing them to normal warfarin metabolism. White people and people of African descent have greater allelic diversity of VKORC1; those of Asian descent are predominantly of the VKORC1AA genotype, 76 the allelic type associated with increased sensitivity to warfarin; and those of African descent are predominantly of the VKORC1BB genotype, the allelic type associated with decreased sensitivity to warfarin. Thus, polymorphisms in CYP2C9 have a larger effect on warfarin dose in white people, whereas VKORC1 polymorphisms affect warfarin dose in white people and people of African and Asian descent, with highest prevalence in those of Asian descent.…”

Section: Discussionmentioning

confidence: 99%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

114

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ADE = adverse drug event; AEI = American Enterprise Institute; ASPE = allele-specific primer extension; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VitKH 2 = vitamin K hydroquinone; VKOR = vitamin K epoxide reductase; VKORC1 = VKOR complex, subunit 1 W arfarin is a well-accepted therapy used for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopedic surgery or with a history of venous or arterial thromboembolism. Many reviews and clinical practice guidelines (summarized by Ansell et al, 1 Baglin et al, 2 Flockhart et al, 3 Husted et al, 4 and Singer et al 5 ) outline the substantial benefits of warfarin therapy for the prevention of strokes in these patients. The American Enterprise Institute (AEI)-Brookings Joint Center for Regulatory Studies Report, which reviewed the use of warfarin in the United States, estimates that approximately 2 million US citizens are prescribed warfarin annually. 6 In 2003, a total of 21.2 million prescriptions were written for oral warfarin in the United States. 7 Warfarin interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K, a cofactor in the γ-glutamyl-carboxylase -mediated activation of coagulation factors II, VII, IX, and X ( Figure 1). The oxidized, inactive form of vitamin K is converted to the reduced form of vitamin K by vitamin K epoxide reductase (VKOR); warfarin inhibits VKOR, resulting in less of the reduced form of vitamin K available to support the factor carboxylation required to sustain the coagulation cascade. 8 Warfarin has a narrow therapeutic index that contributes either to therapeutic failure (potentially leading to stroke or other complications) or therapeutic excess (potentially leading to bleeding and hemorrhage). Many surveys have described the incidence of warfarin-related adverse drugThe antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to ach...

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Section: Discussionmentioning

confidence: 99%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

114

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“…6 This inter-individual variability is known to be affected not only by environmental factor, but also by genetic influence. 5,7 Candidate-gene association studies have identified two genes responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. 8 Several single nucleotide polymorphisms (SNPs) in VKORC1 have been associated with a deficiency in vitamin-K dependent clotting factors, resulting in either increased sensitivity to w-arfarin or warfarin resistance.…”

Section: Introductionmentioning

confidence: 99%

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

et al. 2011

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Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P¼0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (Po0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R 2 ¼0.3499; Po0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients.

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“…Figure 5). [111][112][113][114] Warfarin is a VKA. It is completely absorbed orally, and 98% to 99% is bound to plasma proteins.…”

Section: Food and Drug Interactionsmentioning

confidence: 99%

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease

Giglia¹,

Massicotte²,

Tweddell³

et al. 2013

Circulation

297

245

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Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes

Cited by 131 publications

References 42 publications

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease

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