Genetic and Clinical Predictors of Warfarin Dose Requirements in African Americans

The objective of this study was to determine whether, in African‐American patients, additional vitamin K oxidoreductase complex subunit 1 ( VKORC1 ), cytochrome P450 2C9 ( CYP2C9 ), CYP4F2 , or apolipoprotein E ( APOE ) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9 *2 and *3 alleles and the VKORC1 −1639G>A genotype. In a cohort of 226 African‐American patients, weekly warfarin dose requirements were lower in those with the CYP2C9 *8 allele (34 (30–47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28–40 mg); P < 0.001) as compared with those with the CYP2C9 *1/*1 genotype (43 (35–56) mg). The combination of CYP2C9 alleles, VKORC1 −1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9 *5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1 , CYP4F2 , or APOE polymorphism contributed to the variance. The inclusion of additional CYP2C9 variants may improve the predictive ability of warfarin dosing algorithms for African Americans. Clinical Pharmacology & Therapeutics (2010) 87 4, 459–464. doi: 10.1038/clpt.2009.223