Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction

Abstract

The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G > A), VKORC1*4 (rs17708472/6009 C > T), and CYP4F2 (rs2108622/1347 C > T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n = 105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P = .001 and P = .004, resp.), whereas CYP4F2 (1347 C > T) showed a weak association on higher warfarin dose requirements (P = .09). However, analysing these variant alleles in a regression analysis together with our previously reported data on VKORC1*2, CYP2C9*2 and CYP2C9*3 polymorphisms, gave no significant associations for neither VKORC1*3, VKORC1*4 nor CYP4F2 (1347 C > T). In conclusion, in patients with myocardial infarction, the individual contribution to warfarin dose requirements from VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms was negligible. Our results indicate that pharmacogenetic testing for VKORC1*2, CYP2C9*2 and CYP2C9*3 is more informative regarding warfarin dose requirements than testing for VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms.

Figure 1

Box plot of mean weekly warfarin maintenance dose for combinations of different VKORC1 haplotypes. The boxes represent the values from the 25th to 75th percentile. The middle lines represent the median. The vertical lines extend from the minimum values to the maximam values, excluding outliers and extreme values marked with open circles and asterisk, respectively. The P-value indicates the statistical significance of the difference in mean weekly warfarin dose between patients with or without the VKORC1*2 haplotype (Mann-Whitney test).

Figure 2

Box plot of mean weekly warfarin maintenance dose for combinations of different CYP4F2 genotypes. The boxes represent the values from the 25th to 75th percentile. The middle lines represent the median. The vertical lines extend from the minimum values to the maximum values.