The role of genetic polymorphisms in warfarin anticoagulant therapy

Oralni antikoagulans varfarin se već desetljećima koristi u terapiji i/ili prevenciji tromboembolijskih stanja različite etiologije. Varfarin ima uzak terapijski raspon i pokazuje veliku interindividualnu varijabilnost u odgovoru na terapiju, što može potencijalno rezultirati i po život opasnim komplikacijama uslijed prekomjernog antikoagulacijskog učinka i krvarenja. Cilj ovoga istraživanja bio je ispitati utjecaj polimorfizama VKORC1 -1639G>A, VKORC1 1173C>T, CYP2C9*2, CYP2C9*3, CYP4F2*3 i GGCX 12970C>G te kliničkih i okolišnih čimbenika na stabilnu dozu održavanja i nuspojave terapije varfarinom. U istraživanju su sudjelovala 204 bolesnika na terapiji varfarinom i 420 zdravih ispitanika. Rezultati genotipizacije na zdravim ispitanicima pokazuju kako je učestalost polimorfizama VKORC1 1639G>A i VKORC1 1173>T u populaciji Hrvatske u skladu s učestalošću u europskim populacijama. Rezultati istraživanja na skupini bolesnika na terapiji varfarinom ukazuju na statistički značajnu povezanost stabilne doze održavanja varfarina sa sljedećim čimbenicima: genotipovima CYP2C9, VKORC1 i CYP4F2, zatim s fizičkom aktivnošću, tjelesnom površinom, te uzimanjem lijekova koji utječu na metabolizam varfarina. Algoritam za predviđanje doze dobiven višestrukom linearnom regresijom u stanju je objasniti 49,8 % varijabilnosti doze varfarina. Dokazana je statistički značajna povezanost vremena potrebnog za postizanje stabilne doze varfarina s polimorfizmom CYP4F2*3 te povezanost udjela vremena provedenog unutar terapijskog raspona i pojave nuspojava terapije varfarinom u obliku prekomjerne antikoagulacije s polimorfizmima VKORC1 -1639G>A i/ili VKORC1 1173C>T. Isto tako, utvrđena je statistički značajna povezanost VKORC1 -1639G>A i/ili VKORC1 1173C>T te CYP4F2*3 s nuspojavama terapije varfarinom u obliku krvarenja.Warfarin is the most commonly used oral anticoagulant worldwide. It is used for over a half of century for prevention of thromboembolic disorders. Dosage of warfarin is difficult due to a very narrow therapeutic index (with lifethreatening overdose complications) and wide interindividual variability. Aim of this study was to investigate association of VKORC1 -1639G>A, VKORC1 1173C>T, CYP2C9*2, CYP2C9*3, CYP4F2*3 and GGCX 12970C>G genetic polymorphisms, along with some clinical and environmental factors, on warfarin maintenance dose and adverse effects of warfarin therapy. This study included 204 patients on warfarin therapy and 420 healthy volunteers. Results of genotyping study on healthy population confirms that allele frequencies for VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms in Croatian population are in good agreement with other populations of European ancestry. Results obtained on warfarin patient population indicate that warfarin maintenance dose was significantly associated with following variables: CYP2C9, VKORC1 and CYP4F2 genotype, physical activity, body surface area and concomitant usage of drugs that influence warfarin metabolism. Dosage prediction algorithm obtained with multiple regression could explain 49,8 % of dose variability. Time to warfarin stable dose was significantly associated with CYP4F2*3 genetic polymorphism. Time in therapeutic range was significantly associated with VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms. VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms were also significantly associated with time to first overanticoagulation in warfarin therapy. VKORC1 -1639G>A, VKORC1 1173C>T and CYP4F2*3 polymorphisms were significantly associated with bleedings encountered during warfarin therapy