High Carrier Prevalence of Combinatorial CYP2C9 and VKORC1 Genotypes Affecting Warfarin Dosing

Abstract

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitaminK epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. The CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C) and VKORC1 -1639 G>A polymorphisms affect warfarin dose through altered metabolism (CYP2C9) and sensitivity (VKORC1). We determined the frequencies of SNPs in the CYP2C9 and VKORC1 genes in a clinical outpatient population and the carrier prevalences for a variety of genotype combinations to gauge the impact of these polymorphisms on warfarin dosage using published algorithms. A total of 127 patients from an outpatient clinic at Hartford Hospital (Hartford, CT, USA) were genotyped for five SNPs in the CYP2C9 gene and seven SNPs in the VKORC1 gene using Luminex® technology. The polymorphism frequencies were 10.2, 7.9 and 37.4% for the functionally deficient CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms, respectively. Combining prevalence of combinatorial genotypes, 18% were carriers of both CYP2C9 and VKORC1 polymorphisms, 13% were CYP2C9 polymorphism carriers only, 42.5% were VKORC1 carriers only, and the remaining 27% were noncarriers for either gene. Based on published warfarin dosing algorithms, carriers of 1, 2, 3 and 4 functionally deficient polymorphisms predict reductions of 1.0 to 1.6, 2.0 to 2.9, 2.9 to 3.7, and 3.6 to 4.4mg/day, respectively, in warfarin dose. Overall, 73% of the population carried at least one polymorphism predicting deficient warfarin metabolism or responsiveness and 18% were carriers for polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin amongst patients with gene polymorphisms potentially reducing the risk of accentuated responses and bleeding.