OBJECTIVE: Compared with genetic factors, drug interactions are largely 
unexplored in pharmacogenetic studies. This study sought to systematically 
investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene 
polymorphisms and interacting drugs on warfarin maintenance dose.
METHODS: A retrospective study of 845 Chinese patients after heart valve 
replacement receiving long-term warfarin maintenance therapy was conducted. 
Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may 
interact with warfarin were investigated.
RESULTS: Single-nucleotide polymorphism association analysis showed that VKORC1, 
CYP2C9 and CYP4F2 variations were highly associated with the warfarin 
maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, 
amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, 
and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate 
<0.05). The final pharmacogenetic equation explained 43.65% of interindividual 
variation of warfarin maintenance dose with age, body surface area, VKORC1 
g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem 
accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of 
variation.
CONCLUSION: The present study indicated that VKORC1, CYP4F2, and CYP2C9 
genotypes and interacting drugs had a significant impact on the warfarin 
maintenance dose in Chinese patients with heart valve replacement and 
demonstrated that integrating interacting drugs can largely improve the 
predictability of the dose algorithm.