THE EFFECT OF VITAMIN K EPOXIDE REDUCTASE COMPLEX AND CYTOCHROME P450 GENE POLYMORPHISMS ON WARFARIN DOSE AMONG KURDISH PATIENTS IN DUHOK- IRAQ

Abstract

Background: Warfarin metabolism is subject to a variety of environmental and genetic factorsthat make the response variable among different individuals. These factors include Vitamin Kepoxide reductase complex and cytochrome P450 (CYP2C9) gene polymorphisms. This studywas initiated to address the presence of VKORC 1 -1639G>A and CYP2C9*2,*3 genepolymorphisms and their effects on warfarin drug needed to keep a target InternationalNormalized Ratio (INR) in Kurdish patients from Duhok/Iraq.Methods: Seventy-two patients from the outpatient anticoagulation clinic were enrolled in thisstudy. INR values and required warfarin doses were gained from the clinical records of patientsand their DNA extracted and amplification was done with specific primers for determinationof the VKORC1 -1639G>A and CYP2C9*2,*3 genotypes using restriction fragment lengthpolymorphism technique (PCR-RFLP).Results: Among 72 enrolled patients, 47 were females and the remaining 25 were males witha median age of 55.3 years. The primary causes of anticoagulation were heart valvesreplacement (38.9%), venous thromboembolism (33.3%), arterial thrombosis (23.6%) andmitral valve stenosis (4.2%). Molecular studies revealed that the frequency of VKORC1 -1639G>A variant allele found to be 34.7% and that of CYP2C9*2 and CYP2C9*3 to be 26.4%and 10.4%, respectively.The mean stable therapeutic dose (MSTD) was 3.0 mg/day (20.8 mg/week, range 10.5-56.0mg/week) and patients with CYP2C9*1/1 genotype required significantly larger doses tomaintain their INR within the targets in comparison to other CYP2C9*1/3, CYP2C9*2/2 andCYP2C9*2/3 genotypes with P value of 0.0002, 0.0132 and 0.0080 respectively. Also, patientswith VKORC1 GG genotype required significantly larger doses in comparison to VKORC1GA and VKORC1 AA genotypes with P value of 0.0002 and < 0.0001 respectively.Conclusions: Genetic variability related to warfarin metabolism and clearance determines theresponse to the drug and doses of the drugs to maintain therapeutic INR within the targets.