The largest prospective warfarin-treated cohort supports genetic forecasting

Abstract

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reduc- tase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 can- didate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10-34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P= 9.82 x 10-100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. Dur- ing initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles in- creased the risk of over-anticoagulation, hazard ratios 21.84 (95% Cl 9.46; 50.42) and 4.56 (95% Cl 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3P3 (12.5%) experienced severe bleeding dur- ing the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and drug interactions explained 59% of the vari- ance in warfarin dose, and 53% in an independent sample of 181 Swedish indi- viduals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predis- posed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome. © 2009 by The American Society of Hematology.