Warfarin Response and Vitamin K Epoxide Reductase Complex 1 in African Americans and Caucasians

Schelleman, Hedi; Chen, Zhen; Kealey, Carmel; Whitehead, Alexander S.; Christie, Jason D.; Price, Maureen; Brensinger, C. M.; Newcomb, Craig; Thorn, Caroline F.; Samaha, Frederick F.; Kimmel, Stephen E.

doi:10.1038/sj.clpt.6100144

Cited by 100 publications

(118 citation statements)

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“…Of these patients, 114 (16.0%) were found to be carriers of FVL (83), PTM (25) or both (6). Table 1 reports the main characteristics of the included patients, separately for carriers and non-carriers of these thrombophilic abnormalities.…”

Section: R L E M M E N S * à S a B B O U D § L V A N H E E mentioning

confidence: 99%

“…According to the results of a sub-study of the WODIT clinical trials [3,4], carriers of FVL and PTM seem to have an increased risk of recurrent VTE over non-carriers when the analysis is confined to patients treated for 3 months, whereas this difference is no longer apparent when the analysis includes also patients receiving 1 year of anticoagulation [5]. As we had the opportunity to follow-up over time a large series of consecutive patients who had the determination of FVL and PTM following their initial episode of acute VTE [6,7], we report here on our experience.…”

Section: R L E M M E N S * à S a B B O U D § L V A N H E E mentioning

confidence: 99%

“…Using a candidate gene approach, a common haplotype in the vitamin K epoxide reductase complex subunit 1(VKORC1) gene was found to almost double the vascular (CHD and CVD) risk in a Chinese population [odds ratio (OR) = 1.72, 95% confidence interval (CI) 1.24-2.38 and OR = 1.95, 95% CI 1.58-2.41, respectively] [1]. The same haplotype has been shown to affect mRNA expression of VKORC1 in the liver and thereby the response to warfarin, most likely because of differences in the expression of the protein [2][3][4][5][6][7][8][9]. Indeed, a recent genome-wide scan implicated genetic variants in VKORC1 to be most strongly associated with International Normalized Ratio (INR) response to warfarin [9].…”

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confidence: 99%

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Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease

Lemmens

Abboud

Vanhees

et al. 2008

Journal of Thrombosis and Haemostasis

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Section: R L E M M E N S * à S a B B O U D § L V A N H E E mentioning

confidence: 99%

Section: R L E M M E N S * à S a B B O U D § L V A N H E E mentioning

confidence: 99%

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confidence: 99%

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Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease

Lemmens

Abboud

Vanhees

et al. 2008

Journal of Thrombosis and Haemostasis

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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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“…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. Several variants within the VKORC1 gene have been associated with altered warfarin dose requirements, and haplotypes have been described that are associated with a relatively low hepatic VKORC1 mRNA expression and with lower warfarin dose requirements [43,[47][48][49]. In Caucasians, a single-nucleotide polymorphism (SNP), 1173C/T, was as informative as VKORC1 haplotypes for predicting warfarin dose in a Caucasian population [5] and has been shown to similarly predict dose in African Americans [47].…”

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 Response and Vitamin K Epoxide Reductase Complex 1 in African Americans and Caucasians

Cited by 100 publications

References 23 publications

Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease

Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease

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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