The genetics of vitamin K antagonists

Gage, Brian F.; Eby, Charles S.

doi:10.1038/sj.tpj.6500258

Cited by 15 publications

(9 citation statements)

References 12 publications

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“…GGCX resides in the endoplasmic reticulum membrane and oxidizes reduced vitamin K to vitamin K-2,3-epoxide though carboxylation of the gamma carbon on glutamic acids, thus producing functional vitamin K-dependent clotting factors II, VII, IX, and X (23,24). GGCX-knockout mice die from massive hemorrhaging at birth (25).…”

Section: Discussionmentioning

confidence: 99%

Impact of GGCX polymorphisms on warfarin doserequirements in atrial fibrillation patients

Jiang¹,

Xu²,

Xia³

et al. 2017

Turk J Med Sci

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Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods:Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype. Results:In 215 AF patients, there were 104 cases of wild-type GG genotype (48.4%), 92 cases of GA genotype (42.8%), and 19 cases of AA genotype (8.8%). Patients with the GGCX rs699664 A allele (GA or AA genotypes) needed higher warfarin doses than those with the GG genotype (P < 0.05). A warfarin dosing algorithm showed that age, height, CYP2C9, VKORC1, and GGCX genotype were the best variables for estimating warfarin dose (R2 = 41.2%). Another independent cohort of 60 AF patients showed a significant linear correlation between predicted warfarin maintenance dose and actual dose (R = 0.660, P < 0.01). Conclusion:AF patients with the GA and AA genotypes in GGCX rs699664 required significantly higher warfarin doses. GGCX rs699664 is a potential predictor for the warfarin dose of AF patients.

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Section: Discussionmentioning

confidence: 99%

Impact of GGCX polymorphisms on warfarin doserequirements in atrial fibrillation patients

Jiang¹,

Xu²,

Xia³

et al. 2017

Turk J Med Sci

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“…By impairing the regeneration of the reduced form of vitamin K, R-and S-warfarin interfere with the vitamin-K-dependent carboxylation of clotting factors prothrombin (II), VII, IX, and X. Adapted from [12] Pharmacogenetics of warfarin 47 Clinical and laboratory outcomes associated with VKORC1…”

Section: Clinical Dosing Algorithmsmentioning

confidence: 99%

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Gage

Lesko

2007

J Thromb Thrombolysis

220

135

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Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, -1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007.

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“…Pharmacogeneticbased dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 Warfarin, a member of the coumarin class of oral anticoagulants, is commonly prescribed for primary and secondary prevention of arterial and venous thromboembolic events. 1 Traditionally, warfarin therapy is initiated by empirically selecting a starting dose, frequently monitoring a patient's international normalized ratio (INR), and adjusting the dose until the INR is within the therapeutic range.…”

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confidence: 99%

“…2,3 Considerable progress has been made in identifying clinical, demographic, and genetic components of warfarin dosing variability. 4,5 Based on the present knowledge of genetic factors affecting warfarin pharmacokinetics and pharmacodynamics, 3 common single nucleotide polymorphisms (SNPs) account for approximately 40% of warfarin dosing variability. 6,7 Two SNPs in the cytochrome P-450 2C9 (CYP2C9) gene, *2 and *3, are associated with impaired metabolism of S-warfarin, 8 which is the more potent enantiomer.…”

mentioning

confidence: 99%

Performance of Commercial Platforms for Rapid Genotyping of Polymorphisms Affecting Warfarin Dose

King¹,

Porche-Sorbet²,

Gage³

et al. 2008

Am J Clin Pathol

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Initiation of warfarin therapy is associated with bleeding owing to its narrow therapeutic window and unpredictable therapeutic dose. Pharmacogenetic-based dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 commercial systems: INFINITI analyzer (AutoGenomics, Carlsbad, CA), Invader assay (Third Wave Technologies, Madison, WI), Tag-It Mutation Detection assay (Luminex Molecular Diagnostics, formerly Tm Bioscience, Toronto, Canada), and Pyrosequencing (Biotage, Uppsala, Sweden). We genotyped 112 DNA samples and resolved any discrepancies with bidirectional sequencing. The INFINITI analyzer was 100% accurate for all SNPs and required 8 hours. Invader and Tag-It were 100% accurate for CYP2C9 SNPs, 99% accurate for VKORC1 -1639/3673 SNP, and required 3 hours and 8 hours, respectively. Pyrosequencing was 99% accurate for CYP2C9 *2, 100% accurate for CYP2C9 *3, and 100% accurate for VKORC1 and required 4 hours. Current commercial platforms provide accurate and rapid genotypes for pharmacogenetic dosing during initiation of warfarin therapy.

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The genetics of vitamin K antagonists

Cited by 15 publications

References 12 publications

Impact of GGCX polymorphisms on warfarin doserequirements in atrial fibrillation patients

Impact of GGCX polymorphisms on warfarin doserequirements in atrial fibrillation patients

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Performance of Commercial Platforms for Rapid Genotyping of Polymorphisms Affecting Warfarin Dose

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