Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Warfarin pharmacogenetics.

ABSTRACT: The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing.

SUBMITTER: Johnson JA

PROVIDER: S-EPMC4278947 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Warfarin pharmacogenetics.

Johnson Julie A JA Cavallari Larisa H LH

Trends in cardiovascular medicine 20140906 1

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather t ...[more]

PMID: 25282448

Similar Datasets

Warfarin pharmacogenetics.

Project description:Significant interest in the pharmacogenetics of warfarin therapy has been triggered with the recent package insert update that highlights the potential role of pharmacogenetics in improving the safety and effectiveness of warfarin. We review the evidence of the influence of the two key genes of interest, the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response and discuss the implications of current knowledge for clinical practice. The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials. Dosing algorithms have been developed that incorporate clinical, demographic, and genetic information to help select a warfarin starting dose. Furthermore, CYP2C9 variant genotypes have been associated with a significantly increased risk of serious bleeding events. However, evidence to date from prospective, controlled studies has not demonstrated an added benefit of incorporating genotype-guided therapy in improving anticoagulation control or in preventing or reducing the risk of hemorrhagic or thromboembolic complications. Research efforts designed to evaluate the effectiveness of genotype-guided therapy in improving outcomes are under way. However, the routine use of CYP2C9 and VKORC1 genotyping in the general patient population who begin warfarin therapy is not supported by evidence currently available.

| S-EPMC2756787 | biostudies-literature

Pharmacogenetics of warfarin: challenges and opportunities.

Project description:Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics.

| S-EPMC4074513 | biostudies-literature

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

Project description:This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

| S-EPMC5546947 | biostudies-literature

Warfarin dosage response related pharmacogenetics in Chinese population.

Project description:ObjectivesAs the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.Methods220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.Resultsrs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D': 0.969). 158 of 220 recruited individuals had the target INR (1.5-2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.ConclusionsA better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.

| S-EPMC4296935 | biostudies-literature

Warfarin Pharmacogenetics: New Life for an Old Drug.

Project description:UnlabelledWarfarin was first introduced in the 1950s and quickly became the most commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation, or prosthetic heart valve replacement. Warfarin is highly effective in treating these diseases; however, several factors prevent it from even wider use, especially in Asian populations. It is difficult for patients on warfarin to reach desired anticoagulation due to its narrow therapeutic index and highly variable dose response. The major adverse event is bleeding which is associated with overdose of warfarin. Clinical and genetic factors such as polymorphisms in CYP2C9 and VKORC1 associated with an individual's warfarin maintenance have been identified. More than 20 dose prediction algorithms incorporating both genetic and clinical factors have been developed, and some of them have been tested clinically. However, most of the algorithms were tested in small populations. Several major clinical trials are now underway. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges of clinical implementation of warfarin pharmacogenetics.Key wordsCYP2C9; Pharmacogenetics; VKORC1; Warfarin.

| S-EPMC4804835 | biostudies-literature

Warfarin pharmacogenetics: challenges and opportunities for clinical translation.

Project description: Not available

| S-EPMC3490409 | biostudies-literature

Warfarin pharmacogenetics: does more accurate dosing benefit patients?

Project description:After a decade of clinical investigation, pharmacogenetic-guided initial dosing of warfarin is at a crossroads. Genotypes for two single nucleotide polymorphisms (SNPs) in the cytochrome P 450 2C9 gene, affecting warfarin metabolism, and one SNP in vitamin K reductase complex 1 gene, affecting warfarin sensitivity, account for approximately 30% of therapeutic warfarin dosing variability in whites and Asians. Incorporating this genetic information, along with patient's age, body size, and other clinical information improves the accuracy of initial warfarin dosing. Currently, there is insufficient evidence to support the clinical benefits and cost effectiveness of routine warfarin pharmacogenetics. Results from ongoing international randomized clinical trials should provide clarity about the place of warfarin pharmacogenetics in personalized medicine.

| S-EPMC4407810 | biostudies-literature

The pharmacogenetics of the response to warfarin in Chinese.

Project description:Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1, largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese. Therefore, it is important to recognize and beware of ethnic differences in the pharmacogenetics of the response to warfarin, especially in the design of algorithms to aid dosing in clinical practice.

| S-EPMC3370339 | biostudies-literature

Warfarin pharmacogenetics: How close are we to clinical practice?

Project description: Not available

| S-EPMC3841549 | biostudies-literature

Warfarin anticoagulant therapy: a Southern Italy pharmacogenetics-based dosing model.

Project description:Background and aimWarfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice.Materials and methodsA total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9 2, 3, CYP4F2 3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure.ResultsWarfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9 3 (11.8%), age (8.5%), CYP2C9 2 (3.5%), gender (2.0%) and lastly CYP4F2 3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R(2)?=?0.805 and p<0.001; R(2)?=?0.773, respectively).ConclusionsOur algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy.

| S-EPMC3753327 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data