VKORC1 −1639G&gt;A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement

Puehringer, Helene; Loreth, R. M.; Klose, Gudrun; Schreyer, Brigitte; Krugluger, Walter; Schneider, Barbara; Oberkanins, Christian

doi:10.1007/s00228-010-0809-2

Cited by 19 publications

(21 citation statements)

References 43 publications

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“…Age is a well-known predictor of coumarin dose response [11]. In our study, patients with ages 51–70, 71–80 and 81–92 years needed 23.3%, 38.7% and 46.2% lower daily phenprocoumon doses compared with younger patients.…”

Section: Discussionmentioning

confidence: 56%

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Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

Geisen

Luxembourg

Watzka

et al. 2010

Eur J Clin Pharmacol

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PurposeThe anticoagulation response to vitamin K antagonists is characterised by high inter-individual variability. The impact of single nucleotide polymorphisms (SNPs) in several genes of enzymes involved in the vitamin K cycle on phenprocoumon dose variability and phenprocoumon plasma concentrations is still under investigation.MethodsWe assessed the influence of VKORC1 c.-1639G>A, CYP2C9*2, CYP2C9*3, CYP4F2 c.1297G>A, CALU c.*4A>G, EPHX1 c.337T>C, GGCX c.214+597G>A, F7 c.-402G>A, F7 c.-401G>T, PROC c.-228C>T and PROC c.-215G>A along with clinical and demographic parameters on steady-state phenprocoumon therapy in 75 patients. A prediction model was developed for total phenprocoumon plasma concentrations and daily phenprocoumon doses required for therapeutic anticoagulation.ResultsThe VKORC1 c.-1639 genotype was the main predictor of the phenprocoumon daily dose (adjusted R2 = 37.6%) and the total phenprocoumon concentration (adjusted R2 = 38.3%). CYP2C9 affected the phenprocoumon concentration, but not the dose requirements. SNPs in the other genes of the vitamin K cycle, concomitant medication, nicotine use and alcohol consumption did not predict phenprocoumon concentrations and phenprocoumon dose requirements in a multiple linear regression model. Phenprocoumon concentrations were predicted by VKORC1 c.-1639, CYP2C9 genotype, age and BMI. The final prediction model for the daily phenprocoumon dose requirements comprised VKORC1 c.-1639 genotype, age and height accounting for 48.6% of the inter-individual variability.ConclusionsA rough prediction of phenprocoumon maintenance doses can be achieved by a limited set of parameters (VKORC1, age, height). The investigated SNPs in CYP4F2, CALU, EPHX1, GGCX, F7, and PROC did not improve the predictive value of a pharmacogenetic-based dosing equation for phenprocoumon.

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Section: Discussionmentioning

confidence: 56%

“…Pharmacogenetically-guided dosing formulas have been developed to predict the coumarin maintenance dose [10, 11]. Most of these studies focussed on warfarin, the most widely used coumarin worldwide.…”

Section: Introductionmentioning

confidence: 99%

Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

Geisen

Luxembourg

Watzka

et al. 2010

Eur J Clin Pharmacol

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“…The most frequent variant alleles in Caucasian population, CYP2C9∗2 (rs1799853) and CYP2C∗3 (rs1057910), in the homozygous condition, reduce enzyme activity to 12% and 5%, respectively, compared to the wild-type genotype CYP2C9∗1∗1 . [15–16] The U.S. Food and Drug Administration (FDA) updated the warfarin label, providing dose recommendations based on different combinations of VKORC1 and CYP2C9 genotypes, in 2007 and 2010. [17] Guidelines for clinicians and genetic-based algorithms have been implemented by the International PGx Warfarin Consortium.…”

Section: Introductionmentioning

confidence: 99%

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

et al. 2016

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Vitamin K antagonists (VKAs) are highly effective but have a narrow therapeutic index and require routine monitoring of the INR. The primary aim of pharmacogenetics (PGx) is to optimize patient care, achieving drug treatments that are personalized according to the genetic profile of each patient. The best-characterized genes involved in VKA PGx involve pharmacokinetics (VKORC1) and pharmacodynamics (CYP2C9) of VKA metabolism. The role of these genes in clinical outcomes (bleeding and thrombosis) during oral anticoagulant (OAC) therapy is controversial. The aim of the present study was to evaluate any potential association between genotype VKORC1 and CYP2C9 and adverse events (hemorrhagic and/or thrombotic), during initiation and long-term VKA treatment, in Caucasian patients. Furthermore, we aimed to determine if the concomitant prescription of other selected drugs affected the association between genotype and adverse events.We performed a retrospective, matched case-control study to determine associations between multiple gene variants, drug intake, and any major adverse effects in anticoagulated patients, monitored in 2 Italian anticoagulation clinics.Our results show that anticoagulated patients have a high risk of adverse events if they are carriers of 1 or more genetic polymorphisms in the VKORC1 (rs9923231) and CYP2C9 (rs1799853 and rs1057910) genes.Information on CYP2C9 and VKORC1 variants may be useful to identify individualized oral anticoagulant treatment for each patient, improve management and quality of VKA anticoagulation control, and monitor drug surveillance in pharmacovigilance programs.

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“…Though both genes and environment are widely considered as two major risk factors that cause DVT, numerous genetic analyses of various populations have revealed a close association among genetic factors responsible for the risk of DVT/thromboembolism (2). Coumarins are widely used in therapeutics as anti-coagulants with a narrow range because of variability among individuals in terms of pharmacokinetics and pharmacodynamics due to genetic and environmental factors (3). A patient's response to coumarin is influenced by various factors such as age, sex, vitamin K intake, and medication taken (1,3).…”

Section: Introductionmentioning

confidence: 99%

“…Coumarins are widely used in therapeutics as anti-coagulants with a narrow range because of variability among individuals in terms of pharmacokinetics and pharmacodynamics due to genetic and environmental factors (3). A patient's response to coumarin is influenced by various factors such as age, sex, vitamin K intake, and medication taken (1,3). In addition, defective alleles of certain genes that render individuals to be poor metabolizers of…”

Section: Introductionmentioning

confidence: 99%

Genotyping of <i>CYP2C9</i> and <i>VKORC1</i> polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin

Arunkumar

Vishnuprabu

Nupur

et al. 2017

DD&T

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VKORC1 −1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement

Abstract: Similar to warfarin and acenocoumarol, the VKORC1 -1639G>A polymorphism had the highest impact on the maintenance dose of phenprocoumon. The factor age was the second most important predictor and explained a greater percentage of the variability than CYP2C9 genotype.

Cited by 19 publications

References 43 publications

Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

Genotyping of <i>CYP2C9</i> and <i>VKORC1</i> polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin

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