open access

Vol 68, Supp. V (2010)
Review articles
Published online: 2010-11-25
Submitted: 2012-12-28
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Optimalisation of treatment with vitamin K antagonists - the role of gene polymorphisms

Ewa Stępień, Ewa Wypasek, Agnieszka Branicka, Anetta Undas

open access

Vol 68, Supp. V (2010)
Review articles
Published online: 2010-11-25
Submitted: 2012-12-28

Abstract

The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40-50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 - have been identified and they determined 99% of genetic variability of this enzyme. The presence of -1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8-12% and 3-8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile.
Kardiol Pol 2010; 68, supl. V: 428-435

Abstract

The magnitude of a maintenance vitamin K antagonist (VKA) dose during anticoagulant therapy depends not only on clinical, environmental, and demographic factors, but also on genetic factors. Known genetic polymorphisms explain 40-50% of the variance in VKA dosing. Polymorphisms of two genes encoding enzymes involved in vitamin K and/or VKA metabolism such as vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 isoform (CYP2C9) play a key role in this variance. Polymorphisms of cytochrome P450 4F2 isoform (CYP4F2), apolipoprotein E (APOE) and gamma-glutamyl carboxylase (GGCX) are of minor or negligible importance. In European populations, 3 haplotypes of VKORC1, VKORC1*2, VKORC1*3 and VKORC1*4 - have been identified and they determined 99% of genetic variability of this enzyme. The presence of -1639G>A VKORC1 polymorphism is associated with increased VKA dose requirements. Allelic variants of CYP2C9*2 and CYP2C9*3 (found in 8-12% and 3-8% of individuals, respectively) increase the risk of haemorrhage due to slow VKA metabolism, especially at the therapy initiation. Pharmacogenetic algorithms incorporating VKORC1 and CYP2C9 genotypes help to predict the VKA dosage, particularly if the dose requirements are low or moderate. However, there is no compelling evidence showing reduced risk for clinical adverse events during VKA therapy following the identification of the patient’s genetic profile.
Kardiol Pol 2010; 68, supl. V: 428-435
Get Citation

Keywords

vitamin K antagonists; genetic polymorphism; vitamin K epoxide reductase; cytochrome P450; resistance; pharmacogenetics; stable anticoagulation

About this article
Title

Optimalisation of treatment with vitamin K antagonists - the role of gene polymorphisms

Journal

Kardiologia Polska (Polish Heart Journal)

Issue

Vol 68, Supp. V (2010)

Pages

428-435

Published online

2010-11-25

Keywords

vitamin K antagonists
genetic polymorphism
vitamin K epoxide reductase
cytochrome P450
resistance
pharmacogenetics
stable anticoagulation

Authors

Ewa Stępień
Ewa Wypasek
Agnieszka Branicka
Anetta Undas

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