VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: Interaction between both genotypes affects overanticoagulation

Schalekamp, Tom; Brassé, Bjorn P.; Roijers, Janine F. M.; Chahid, Youssef; Geest-Daalderop, Johanna H. H. van; Vries-Goldschmeding, Hanneke de; Wijk, E. M. van; Egberts, Toine C. G.; Boer, Anthonius de

doi:10.1016/j.clpt.2006.04.006

Cited by 132 publications

(145 citation statements)

References 48 publications

(109 reference statements)

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“…Although the focus of the current study was to define the association of CYP2C9 genotype on warfarin dose and risk of complications we recognize that drug response is influenced by multiple genes. [44] [45,46] At least one other gene; Vitamin K Epoxide Reductase (VKORC1) has been consistently shown to significantly influence warfarin dose in European Americans [14,15,47,48] and recently among African Americans. [49] Expansion of genotyping efforts, within this prospective cohort, to include other genes along the warfarin pharmacodynamic and pharmacokinetic pathways will facilitate gene-gene interaction studies and help tailor warfarin therapy based on genetic, clinical and demographic characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…However, most of these efforts have focused on populations of European descent. [11][12][13][14][15][16][17][18]Herein we report CYP2C9 allele frequencies among European American and African American patients and evaluate the influence of CYP2C9 on warfarin dose stratified by race. We detail genotyping methodology and describe study design and cohort characteristics at enrollment.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awareness in the clinical community.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Cooper

Johnson

Langaee³

et al. 2008

Blood

403

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Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n ‫؍‬ 181) and 2 independent replication patient populations (n ‫؍‬ 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P ‫؍‬ 6.2 ؋ 10 ؊13 ) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ϳ 10 ؊4 ). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. IntroductionThe determination of safe yet effective doses of warfarin for individual patients is one of the most promising clinical applications of pharmacogenetics. [1][2][3] There are large variation in warfarin dose from patient to patient and significant clinical consequences of doses that produce insufficient or excessive pharmacologic effects. Thus, reducing uncertainty in establishing the therapeutic dose in individual patients could improve quality of care as well as expand the range of patients who could be treated. 4 In white patients, genetic factors are more strongly correlated with stabilized warfarin dose than all other known patient-related factors. Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awar...

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“…The short half-life of acenocoumarol in combination with the short half-life of factor VII [15], and the intake of a dose algorithm with uneven daily doses of acenocoumarol [16] also may have an effect on the INR. Moreover, recently the genotypes of both the systems CYP2C9 and VKORC1 have been found to influence the stability and dose of VKAs [17][18][19]. Polymorphisms of one genotype or of a combination of both genotypes show a higher risk of excessive anticoagulation, a decreased chance to achieve stability and a lower dose requirement.…”

Section: Discussionmentioning

confidence: 99%

Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model

Geest-Daalderop

Hutten

Péquériaux

et al. 2008

J Thromb Thrombolysis

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Background In a retrospective study we have developed a model which determines the dose of acenocoumarol based on the age of the patient and on the first INR obtained after a standard initial loading dose. The group of patients of this study was used as the control group of the present study. Aim The aim of this study was to prospectively validate the model and to assess whether the use of this model improves the quality of the treatment in the 0-2 months study period. Patients and methods In 197 patients the model was evaluated by (1) in the initial phase: comparison of INRs with the control group, after assessing the dose according to the model, and (2) in the 0-2 months period: calculation of the percentage of time spent in the therapeutic target range compared to the control group. Furthermore, the eventual dose was compared to the dose of the model when the INRs were within the therapeutic target range for the first time and on two successive occasions. Results (1) When dosed according to the model, 50% of INRs in the total group were within the therapeutic target range compared to 45% in the control group, and (2) the percentage time spent within this range was 68 in the total group compared to 63 in the control group (P = 0.0013). When the INRs were within the range for the first time and successively twice, the eventual doses were similar to the model in 59 and 50%, respectively. About 20% of the patients did not achieve two successive INRs within the range. Conclusions Using the model the quality of treatment improved. We advice to use a standardized individualized dose regimen at the initiation of vitamin K antagonist treatment.

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VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: Interaction between both genotypes affects overanticoagulation

Abstract: Being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than of one of these polymorphisms, is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype.

Cited by 132 publications

References 48 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

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Improvement in the regulation of the vitamin K antagonist acenocoumarol after a standard initial dose regimen: prospective validation of a prescription model

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