title: [Optimalisation of treatment with vitamin K antagonists--the role of gene polymorphisms].
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.
authors.affiliation: Krakowski Szpital Specjalistyczny im. Jana Pawła II, Kraków.
authors.forename: Ewa
authors.initials: E
authors.lastname: Stępień
authors.forename: Ewa
authors.initials: E
authors.lastname: Wypasek
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Branicka
authors.forename: Anetta
authors.initials: A
authors.lastname: Undas
mesh_terms: D000933:Antifibrinolytic Agents / Q000008:administration & dosage*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000502:physiology*; D016032:Randomized Controlled Trials as Topic; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases
chemical_list: D000933:Antifibrinolytic Agents; D014812:Vitamin K; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C084930:cytochrome P-450 2C2; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases