CYP2C0, VKORC1 and CYP4F2 Variant Frequencies in Patients on either Low or High Stable Warfarin Maintenance Therapy in the Ghanaian Population

Abstract

Warfarin is the most commonly prescribed oral anticoagulant drug for reducing thromboembolic events that often give rise to stroke, deep vein thrombosis, pulmonary embolism, or serious coronary malfunctions. Warfarin has a narrow therapeutic / toxic ratio and genetic factors have been associated with inter-individual variability in warfarin dose / response in different ethnic populations. The initiation of this drug has been associated with one of the highest adverse event rates for any single drug, particularly in the elderly. The aim of this study was to determine the frequency of CYP2C9, VKORC1 and CYP4F2 variant alleles in the Ghanaian population as bases to estimate the potential impact of these polymorphisms on warfarin maintenance dose. The study also sought to determine the clinical and demographic factors associated with warfarin maintenance dose in indigenous Ghanaian patients. One hundred and forty three adult Ghanaian patients on stable warfarin therapy at the Korle-Bu Teaching Hospital were genotyped for CYP2C9 (*2, *3), CYP4F2 rs2108622, and VKORC1_1639G > A polymorphisms using PCR-RFLP assay methods. The most common indications for warfarin use were valve replacement (n = 63, 44%), deep vein thrombosis (n = 52, 36.4%), pulmonary embolism (n = 18, 12.6%), and atrial fibrillation (n = 10, 7.0%). Warfarin dose was negatively correlated with patient age but not statistically significant (r = -0.024, 95% CI (-0.052-0.004), p = 0.090). Women were found to be taking a higher mean daily warfarin dose of 5.75mg (95% CI, 5.174-6.326) than males who took 5.46mg (95% CI, 4.907-6.022) although this was not statistically significant, p = 0.479). Warfarin dose was positively correlated with patient height but not statistically significant (r = 0.010, [-0.031-0.052], p = 0.630). BMI was found to have no influence on mean daily warfarin dose (OR: 0.571, p = 0.513) in this study population. Allelic frequencies for CYP2C9*3 were observed at (23%) while genotype frequencies for CYP2C9*3 were observed at (10.87%). CYP2C9*2 alleles and genotypes were not detected in this study population. Allele frequencies for VKORC1_1639A were observed at (6%) however, the VKORC1_1639A genotype was not detected in this study. Allele frequencies for CYP4F2 rs2108622 (T) was observed at (41%) and its genotype (T/T) frequencies were observed at (6.84%). According to the combined effect of the CYP2C9, VKORC1 and CYP4F2 genotypes, patients having the wild-type (*1/*1) genotype of CYP2C9 in combination with the homozygous mutant (T/T) genotype of CYP4F2 and the wild-type (G/G) genotype of VKORC1 required the highest mean daily warfarin dose of 7.50mg/day (95% CI, 7.50-7.50, p = 0.096). It was also observed that patients with a combination of CYP2C9 wild-type (*1/*1), CYP4F2 wild-type (C/C) and VKORC1 wild-type (G/G) genotypes were treated with the lowest mean daily warfarin dose of 4.79mg/day (95% CI, 3.02-6.55, p = 0.096). Interestingly, carriers of the heterozygous genotype of CYP2C9*1/*3, and CYP4F2 (C/T), and VKORC1 wild-type (G/G) genotype were given 6.50mg (95% CI, 5.40-7.60, p = 0.027). This study has established for the first time the combined effect of genotypes of CYP2C9, VKORC1 and CYP4F2 genes on mean daily warfarin dose in Ghanaian patients. VKORC1 and CYP4F2 variant alleles to our knowledge are being reported for the first time among the indigenous Ghanaian population.