Influence of CYP2C9 genotype on warfarin dose among African–Americans and European–Americans

Abstract

Background: Cytochrome P450 (CYP)2C9 plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and to determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European–American and African–American patients. We also identify two new mutations, one in the coding region and one in the noncoding region of the CYP2C9 gene. Methods: Patients (aged >20 years) were enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in international normalized ratio, warfarin dose, co-medications, diet, physical activity and the occurrence of complications were documented. CYP2C9 genotype was determined using PCR with restriction fragment length polymorphisms, and pyrosequencing. Differences in genotype frequencies and Hardy–Weinberg equilibrium assumptions were assessed using χ² statistics and exact tests. The genotype–dose association was evaluated using multivariable linear regression. Results: This report includes 490 patients (mean age: 60.6 ±15.6 years; 51.3% men). African–American patients comprised 48.9% of the cohort, with a mean follow-up of 13.5 (±10.6) months. Both the CYP2C9*2 and *3 allele were more frequent in European–Americans (11.24 and 5.1%, respectively) compared with African–Americans (1.1 and 1.8%). CYP2C9*5 (0.9%), *6 (0.4%) and *11 (1.1%) variants were only observed in African–Americans. The variant genotype is more frequent among European–Americans compared with African–Americans (29.8 vs 9.73%; p < 0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p < 0.0001), both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European–American but not among African–American patients. Conclusion: The variant CYP2C9 genotype is more frequent among European–Americans compared with African–Americans. Among African–Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European–Americans, but not in African–Americans.