Warfarin and Cytochrome P450 2C9 Genotype: Possible Ethnic Variation in Warfarin Sensitivity

Kealey, Carmel; Chen, Zhen; Christie, Jason D.; Thorn, Caroline F.; Whitehead, Alexander S.; Price, Maureen; Samaha, Frederick F.; Kimmel, Stephen E.

doi:10.2217/14622416.8.3.217

Cited by 53 publications

(77 citation statements)

References 25 publications

(20 reference statements)

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“…It also confirms recently findings by Kealey et al [33] on the lack of significant influence of CYP2C9*2 and CYP2C9*3 on warfarin dose in African Americans. Our findings further extend this lack of association after inclusion of CYP2C9*5, *6 and *11 among African American patients.…”

Section: Discussionsupporting

confidence: 92%

“…Inclusion of rare alleles such as CYP2C9*5, CYP2C9*6 and CYP2C9*11 resulted in the variant genotype frequencies to be higher among African Americans (5.3%) than previously reported (3.7%) for this population. [9,33] As previously reported CYP2C9*2 and CYP2C9*3 were the most common poormetabolizer CYP2C9 alleles, among both European American and African American patients, although the frequency of these alleles was higher in the former group. The allele frequencies for CYP2C9*2 and CYP2C9*3 are consistent with those reported previously.…”

Section: Discussionmentioning

confidence: 66%

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Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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Background-Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 66%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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“…Several studies have cast doubt that the -1639G allele is responsible for warfarin dosing variability in people of African origin. [36][37][38] Other alleles in VKORC1 may affect warfarin dosing, such as the mild to moderate increase in warfarin dose associated with the Asp36Tyr amino acid substitution. 39 The combined interaction of the cytochrome P450 2C9 isoenzyme (CYP2C9) and VKORC1 on warfarin's anticoagulant activity is shown in Figure 2.…”

Section: Incidence Of Warfarin-related Adesmentioning

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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“…CYP2C9 is largely responsible for the metabolic clearance of (S)-warfarin, the more active of the two CYP2C9 isoforms [36], accounting for 60 -70% of warfarin's overall anticoagulant activity [37]. Two variants within CYP2C9, designated * 2 and * 3, are clearly associated with lower warfarin dose requirements in Caucasian populations and increased bleeding risk [38][39][40][41][42][43][44][45]. However, their effect is less clear in other populations, particularly African Americans [44,46].…”

Section: Reasons For Difficulty With Warfarin Therapymentioning

confidence: 99%

“…Two variants within CYP2C9, designated * 2 and * 3, are clearly associated with lower warfarin dose requirements in Caucasian populations and increased bleeding risk [38][39][40][41][42][43][44][45]. However, their effect is less clear in other populations, particularly African Americans [44,46]. VKORC1 is the warfarin-sensitive and rate-limiting enzyme of the vitamin K cycle that recycles the epoxide and quinone form of vitamin K to the reduced non-oxidized form.…”

Section: Reasons For Difficulty With Warfarin Therapymentioning

confidence: 99%

Warfarin therapy: in need of improvement after all these years

Kimmel

2008

Expert Opinion on Pharmacotherapy

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Background-Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal.Objective-To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy.Results-Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions.Conclusion-Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes.

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Warfarin and Cytochrome P450 2C9 Genotype: Possible Ethnic Variation in Warfarin Sensitivity

Abstract: CYP2C9 2 and 3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.

Cited by 53 publications

References 25 publications

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

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

Warfarin therapy: in need of improvement after all these years

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Warfarin and Cytochrome P450 2C9 Genotype: Possible Ethnic Variation in Warfarin Sensitivity

Abstract: CYP2C9 *2 and *3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.

Cited by 53 publications

References 25 publications

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

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

Warfarin therapy: in need of improvement after all these years

Contact Info

Product

Resources

About

Abstract: CYP2C9 2 and 3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.