Author/Editor		Herman, Darja
Title		Vpliv genetskega polimorfizma CYP2C9 na presnovo varfarina in na učinkovitost antikoagulacijskega zdravljenja
Translated title		The influence of CYP2C9 genetic polymorphism on warfarin metabolism and anticoagulant treatment
Type		monografija
Place		Ljubljana
Publisher		Univerza v Ljubljani, Medicinska fakulteta
Publication year		2006
Volume		str. 115
Language		slo
Abstract		Background: Warfarin is the most common anticoagulant drug used in Slovenia. Due to its narrow therapeutic index and high interindividual variability in the dose required to achieve the desired therapeutic effect careful monitoring of prothrombin time is necessary. Warfarin inhibits vitamin K epoxide reductase (VKOR), which recycles vitamin K 2,3 epoxide to reduced vitamin K. The reduced vitamin K is a required cofactor for the y-glutamyl carboxylase (GGCX) that converts precursor forms of blood clotting factors FII, FVII, FIX, FX and endogenous anticoagulant proteins C, S and Z to active zymogens. The predominant enzyme that metabolizes S-warfarin to 7-hydroxywarfarin is cytochrome P450 2C9 (CYP2C9). Human CYP2C9 gene is highly polymorphic. Beside the wild-type CYP2C9*1 allele the two most common variant alleles in Caucasian populations are CYP2C9`2 and CYP2C9*3. It was demonstrated in vitro and in vivo that these two allelic variants of CYP2C9 gene influenced the metabolic activity of the enzyme. Genes for vitamin K-dependent blood coagulation factors, as well as GGCX and VKOR are also polymorphic, and could influence warfarin pharmacodynamics. Aims: The aim of our study was to analyze the influence of various genetic factors, especially CYP2C9 gene polymorphisms, on warfarin treatment. First, we focused on the common polymorphisms in CYP2C9 gene which give rise to proteins with altered catabolic activity and then all exons and intron-exon boundaries of CYP2C9 gene were screened in order to identify new sequence variations. We were also interested in the effect of concomitant drug treatment and demographic factors on warfarin metabolism and its maintenance dose. The objective of our study was also to determine whether polymorphisms in genes involved in blood coagulation (VKOR, GGCX and FVII) influence interindividual variability in warfarin dose requirement. (Abstract truncated at 2000 characters)
Descriptors		ANTICOAGULANTS WARFARIN POLYMORPHISM (GENETICS) CYTOCHROME P-450 EXONS INTRONS ALLELES GENOTYPE POINT MUTATION POLYMERASE CHAIN REACTION POLYMORPHISM, SINGLE-STRANDED CONFORMATIONAL TREATMENT OUTCOME