Uloga genskih polimorfizama u antikoagulacijskoj terapiji varfarinom

doctoral thesis

• Title (english): The role of genetic polymorphisms in warfarin anticoagulant therapy
• Author: Dario Mandić
• Mentor: Lada Rumora (mentor)
• Mentor: Nada Božina (komentor); MBZ: 91773
• Committee member: Karmela Barišić (predsjednik povjerenstva)
• Committee member: Vesna Bačić Vrca (član povjerenstva)
• Committee member: Mario Štefanović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2017, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

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.

Abstract (english)

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.

• Keywords: varfarin; antikoagulacijska terapija; genski polimorfizmi; VKORC1; CYP2C9; CYP4F2; GGCX
• Keywords (english): warfarin; anticoagulation therapy; genetic polymorphisms; VKORC1; CYP2C9; CYP4F2; GGCX
• Language: croatian
• URN:NBN: urn:nbn:hr:163:731264
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-11-30 16:42:28