Association of warfarin dose with genes involved in its action and metabolism

Wadelius, Mia; Chen, Leslie Y.; Eriksson, Niclas; Bumpstead, Suzannah; Ghori, Jilur; Wadelius, Claes; Bentley, David; McGinnis, Ralph; Deloukas, Panos

doi:10.1007/s00439-006-0260-8

Cited by 333 publications

(322 citation statements)

References 68 publications

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“…SNPs near CYP2C9 were more modestly associated with warfarin dose, with a number of correlated variants less than or equal to 10 Ϫ4 . For example, rs4917639, which has been shown previously to effectively tag both the *2 and *3 nonsynonymous variants, 17 had a P value of 9.7 ϫ 10 Ϫ5 . Polymorphisms within 100 kb of 30 well-studied candidate genes did not show any association when examining the lowest univariate P values in the region (Table 2).…”

Section: Regression Resultsmentioning

confidence: 99%

“…However, we attempted to replicate all sites of variation that produced a P value less than 10 Ϫ4 in the index population; we included a polymorphism if it achieved this level of significance in any of the effect models tested (univariate, multivariate, additive, dominant/recessive, and interaction). We also attempted to replicate any variant within 500 kb of a previously defined candidate gene 17 if it achieved a P value of less than 10 Ϫ3 in any tested model. For the replication analysis, a P value of 10 Ϫ4 (roughly equivalent to a Bonferroniadjusted [355 tests] P value of .05) was established as a cutoff for confirmation in the replication population.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we included SNPs that had P values less than 10 Ϫ3 if they were within 500 kb of one of 30 candidate genes that had been previously proposed to be important to warfarin metabolism and/or mode of action. 17 After scoring for assay suitability, some replication SNPs could not be genotyped in this assay. Twenty-nine SNP assays of 384 failed to yield high-quality genotypes, leaving 355 to be analyzed in the replication samples.…”

Section: Replication Genotypingmentioning

confidence: 99%

“…Other warfarin candidate genes that are part of the vitamin K pathway, vitamin K-dependent clotting factors, or minor metabolic or transport pathways have been systematically screened, with only VKORC1 and CYP2C9 reaching significance. 17 Generally, dose associations with other candidate genes have shown small statistical effects or fail to replicate in independent populations. 15,18,19 It remains unclear whether additional common genetic variation outside of these candidate genes contribute significantly to the 45% to 55% of unexplained variance in warfarin dosing.…”

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confidence: 99%

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

Cooper

Johnson

Langaee³

et al. 2008

Blood

403

302

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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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Section: Regression Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Replication Genotypingmentioning

confidence: 99%

mentioning

confidence: 99%

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

Cooper

Johnson

Langaee³

et al. 2008

Blood

403

302

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“…Combined, polymorphisms in these 2 alleles plus age, sex, and weight account for 56% to 64% of warfarin dose variation. 56,[73][74][75] Table 7 summarizes the effects of CYP2C9 and VKO-RC1 variants on warfarin dose, the effects these variants have on sensitivity to warfarin, and variant prevalence as observed and reported in 3 previously published peerreviewed reports plus results from the current report (835 patients total). The findings from these 4 unrelated studies describing the association between warfarin daily dose and genotype show considerable agreement.…”

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

112

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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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Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

Dolžan

2012

Pharmacogenetics and Individualized Therapy

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Association of warfarin dose with genes involved in its action and metabolism

Cited by 333 publications

References 68 publications

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

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

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

Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

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