Abstract
Genetic variants of cytochrome P450 2C9 (
CYP2C9
) and vitamin K epoxide reductase (
VKORC1
) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response.
CYP2C9
*2 and *3 explained 12% (
P
= 6.63 × 10
−34
) of the variation in warfarin dose, while a single
VKORC1
SNP explained 30% (
P
= 9.82 × 10
−100
). No SNP outside the
CYP2C
gene cluster and
VKORC1
regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for
CYP2C9
and
VKORC1
variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with
CYP2C9
*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (
P
= .066). A multiple regression model using the predictors
CYP2C9, VKORC1
, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion,
CYP2C9
and
VKORC1
significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.