The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin

Abstract

Differences in warfarin maintenance dosages based on the presence of polymorphisms in VKORC1, CYP2C9, CYP4F2, and ORM1 can be determined through dosage adjustment according to routine guidelines. Little is known about whether routine therapy could provide consensus anticoagulation control for patients with different genotypes. This study was carried out to compare anticoagulant control in patients with different genotypes. Six hundred seventy patients using warfarin according to Chinese guidelines were enrolled. Warfarin dosages and monitored international normalized ratios (INRs) were recorded. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622, CYP2C9 rs1057910, and ORM1 rs17650 polymorphisms were determined. Warfarin dosages and INR were compared between genotypes. Patients with the AGCC*F*F*1*1 polymorphism took longer than patients with the AACC*F*F*1*1 polymorphism (20 vs 5 days, P < .001) to achieve the targeted INR range. The INR values of patients with AACC*F*F*1*3 were unstable and did not enter the stable state control phase until after 35 days. The peak INR of patients with the AACC*F*F*1*3 polymorphism was exceedingly high, with some values exceeding the control range limit of 3.0. Patients with the AACC*F*S*1*1 or AACT*F*F*1*1 polymorphisms exhibited similar INR values as the patients with the AACC*F*F*1*1 polymorphism. This study found that routine medication with warfarin provides significantly different levels of anticoagulant control between patients with wild-type genotypes and patients with heterozygous polymorphism genotypes of VKORC1 rs9923231 or CYP2C9 rs1057910. Patients with heterozygous polymorphism genotypes of VKORC1 or CYP2C9 require genotype-directed therapy with warfarin to increase efficacy and safety in anticoagulant treatment.

Keywords: CYP2C9; CYP4F2; ORM1; VKORC1; warfarin.

Figure 1.

Box plot distributions of warfarin dosage taken by patients with wild-type genotype and heterozygous polymorphism genotypes of CYP2C9 rs1057910, ORM1 rs17650, CYP4F2 rs2108622, and VKORC1 rs9923231. Boxes: median and interquartile range of the 25th to 75th percentiles, vertical lines above and below boxes: maximum and minimum values, respectively. The maximum length of each whisker is 1.5 times the interquartile range. Each outlier is denoted with a circle and a data number.

Figure 2.

Comparison of the curves of INR between patients with wild-type genotype and heterozygous polymorphism genotypes of VKORC1 rs9923231 (A), CYP2C9 rs1057910 (B), CYP4F2 rs2108622 (C), and ORM1 rs17650 (D).

Figure 3.

Comparison of the proportion of patients who did not reach the target INR therapeutic range between patients with wild-type genotype and heterozygous polymorphism genotypes of VKORC1 rs9923231 (A), CYP2C9 rs1057910 (B), CYP4F2 rs2108622 (C), and ORM1 rs17650(D).