Abstract
We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes
VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX
and
ORM1-ORM2
and haplotypes of
VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2
and
ORM1
-
ORM2
were associated with dose (
P
< 0.05).
VKORC1, CYP2C9, CYP2C18
and
CYP2C19
were significant after experiment-wise correction for multiple testing (
P
< 0.000175), however, the association of
CYP2C18
and
CYP2C19
was fully explained by linkage disequilibrium with
CYP2C9*2
and/or
*3
.
PROC
and
APOE
were both significantly associated with dose after correction within each gene. A multiple regression model with
VKORC1, CYP2C9, PROC
and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin.