VKORC1 Pharmacogenomics Summary

Owen, Ryan; Gong, Li; Sagreiya, Hersh; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e32833433b6

Cited by 103 publications

(71 citation statements)

References 28 publications

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“…The most frequent and most deeply studied polymorphisms are VKORC1 -1639G>A and 1173C>T. These SNPs, in the promotor and fi rst intron of VKORC1 gene infl uence the enzymatic activity of VKOR (17) which is an enzyme in vitamin K cycles and the pharmacological target of coumarins (18). VKORC1 1173C>T, rs9934438 is in almost complete linkage disequilibrium with the polymorphism of VKORC1 -1639G>A, rs9923231 where both associate with increased sensitivity to warfarin (16). These SNPs are responsible for 30 % of interindividual variability in warfarin treatment (7).…”

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confidence: 99%

“…Common polymorphisms in the regulatory region of VKORC1 gene correlate strongly with warfarin response across the normal dosing range (15). Polymorphisms in VKORC1 gene signifi cantly change the pharmacodynamics and dosage adequacy of warfarin (16). The most frequent and most deeply studied polymorphisms are VKORC1 -1639G>A and 1173C>T. These SNPs, in the promotor and fi rst intron of VKORC1 gene infl uence the enzymatic activity of VKOR (17) which is an enzyme in vitamin K cycles and the pharmacological target of coumarins (18).…”

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confidence: 99%

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Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Krajčíová¹,

Déžiová²,

Petrovič³

et al. 2014

BLL

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Objectives: The study was aimed at establishing an effective molecular-genetic method for detecting polymorphisms in genes CYP2C9 and VKORC1, which affect the pharmacogenetics of warfarin, and at determining their prevalence in Slovak population. Background: Warfarin, derivative of coumarin, belongs to the most commonly prescribed oral anticoagulants with narrow therapeutic index. An insuffi cient dose of warfarin can result in failure to produce the antithrombotic effect, whereas an overdose increases the risk of bleeding. It was proven that genetic variability in two genes, CYP2C9 a VKORC1, has a signifi cant infl uence on the individual's response to the dosage of warfarin. Methods: In a control group of 112 randomly selected individuals, we tested the frequency of selected single nucleotide polymorphisms including CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), VKORC1*2 (1173C>T) by allele-specifi c Real-Time PCR and VKORC1*2 (-1639G>A) by using PCR-RFLP. Results: Due to the combination of frequent alleles CYP2C9*2, CYP2C9*3 and VKORC1*2 in Slovak population we determine that 25% of population need a standard 5-mg daily dose of warfarin, while 44%, 23%, and 8% need 4 mg, 3 mg and 2 mg of warfarin per day. Conclusion: Slovak population is in Hardy-Weinberg equilibrium and frequencies of SNPs were in accordance with other published results in European populations (Tab. 5. Fig. 3, Ref. 51). Text in PDF www.elis.sk.

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confidence: 99%

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confidence: 99%

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Krajčíová¹,

Déžiová²,

Petrovič³

et al. 2014

BLL

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“…Polymorphisms in vitamin K epoxide reductase gene and cytochrome P450 type 2C9 (CYP2C9) are not race specific, and they account for 25% and 10%, respectively, of the interindividual variability in warfarin dosing (6). Vitamin K epoxide reductase genotype may be the best predictor of warfarin dose, because it is responsible for the conversion of vitamin K epoxide to vitamin K ( Figure 1) (6). CYP2C9 alleles (e.g., CYP2C9*2 and *3) are poor metabolizers, leading to prolonged t 1/2 compared with the wild type (*1 allele) (5).…”

Section: Warfarin Pharmacologymentioning

confidence: 99%

Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

Jain¹,

Reilly²

2018

CJASN

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Oral anticoagulants are commonly used drugs in patients with CKD and patients with ESKD to treat atrial fibrillation to reduce stroke and systemic embolism. Some of these drugs are used to treat or prevent deep venous thrombosis and pulmonary embolism in patients with CKD who undergo knee and hip replacement surgeries. Warfarin is the only anticoagulant that is approved for use by the Food and Drug Administration in individuals with mechanical heart valves. Each oral anticoagulant affects the coagulation profile in the laboratory uniquely. Warfarin and apixaban are the only anticoagulants that are Food and Drug Administration approved for use in patients with CKD and patients with ESKD. However, other oral anticoagulants are commonly used off label in this patient population. Given the acquired risk of bleeding from uremia, these drugs are known to cause increased bleeding events, hospitalization, and overall morbidity. Each anticoagulant has unique pharmacologic properties of which nephrologists need to be aware to optimally manage patients. In addition, nephrologists are increasingly asked to aid in the management of adverse bleeding events related to oral anticoagulant use in patients with CKD and patients with ESKD. This article summarizes the clinical pharmacology of these drugs and identifies knowledge gaps in the literature related to their use.

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“…5,[14][15][16] On the other hand, VKORC1 encodes vitamin K epoxide reductase 1 17 (which is the target of VKA), and rs9923231 located at promoter of the gene, drives its transcription levels. 18 By this reason, polymorphisms in these two genes have been involved in the pharmacogenetics of VKAs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Serna

Rivera‐Caravaca

Gónzález-Conejero

et al. 2018

Eur J Clin Investigation

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Background: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. Material and methods: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded. Results: During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. Conclusion: Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding. K E Y W O R D Satrial fibrillation, CYP2C9, haemorrhage, polymorphisms, VKORC1 Serna and Rivera-Caravaca equally contributed to this study. Rold an and Mar ın are joint senior authors.

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VKORC1 Pharmacogenomics Summary

Cited by 103 publications

References 28 publications

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice

Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

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