THE EFFECT OF GENETIC AND NON-GENETIC FACTORS ON WARFARIN DOSE VARIABILITY IN QATARI POPULATION

Abstract

Introduction: Genetic and non-genetic factors were shown to affect warfarin dosing; however, their effect may vary from one population to the other. No previous studies were conducted on the Qatari population to elucidate these factors. Research question: What is the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants in Qataris? and what is their contribution to warfarin dose variability? Study design: An observational cross-sectional study Methods: Hundred and fifty warfarin-treated Qatari patients on a stable dose and a therapeutic INR for at least 3 consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. Results: The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A 0.46, while the MAF’s for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one loss of function CYP2C9 allele (*2 or *3) required significantly lower warfarin doses compared to non-carriers (24 mg/week vs. 34.1 mg/week, p<0.001). VKORC1 (-1639G>A) and CYP4F2*3 polymorphisms on the other hand were not associated with warfarin dose. Multivariate analysis on the derivation cohort showed that congestive heart failure (CHF) (P=0.002), and CYP2C9*2 & *3 (P<0.001) were associated with lower warfarin dose while smoking (P=0.003) was associated with higher warfarin dose. These factors explained 24.1% of warfarin dose variability in Qatari patients. CYP2C9*2 & *3 variants accounted for 11.8% of warfarin dose variability. In the validation cohort, correlation between predicted and actual warfarin doses was moderate (Spearman’s rho correlation coefficient= 0.41, p=0.005). Conclusion: This study showed that CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with CHF and smoking. Dose reduction should be considered in patients with CHF and those carrying at least one of the CYP2C9*2 & *3 alleles. While dose increase should be considered in smokers