Novel CYP2C9 and VKORC1 Gene Variants Associated with Warfarin Dosage Variability in the South African Black Population

Abstract

Warfarin is a widely used therapeutic agent for long-term oral anticoagulation worldwide. Its administration is challenging owing to its narrow therapeutic range and serious adverse effects. Several environmental factors and numerous genes, of which CYP2C9 and VKORC1 are the most important, have been associated with interindividual dosage variability. Many studies have been conducted to understand warfarin dosage variability better, the majority of which have been focused on the Caucasian and African-American populations. Very little information is available regarding genetic influences of warfarin dosage variability in the South African black population. In this study, we genotyped 213 South African black individuals for CYP2C9 and VKORC1 variants and a small subset of environmental factors that may be responsible for warfarin dosage variability. We observed 26 novel SNPs and seven previously described CYP2C9 variants and three previously described but no novel VKORC1 SNPs. Only 11 of the CYP2C9 variants and two of the VKORC1 variants were observed at high enough allele frequencies to assess their impact on warfarin dosage. We demonstrate that CYP2C9*8 and two novel CYP2C9 SNPs (g.16179 and g.46028) are associated with a decrease in warfarin dosage, β-blockers are independently associated with a decrease in warfarin dosage and two known VKORC1 variants (rs7200749 and rs7294) are associated with an increase in warfarin dosage. The CYP2C9 and VKORC1 variants and a small subset of environmental factors used in the study explain approximately 45% of warfarin dosage variability in the South African black population.