VKORC1-1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement

Phenprocoumon, similar to other coumarin-derived anticoagulants, is associated with a large variation in the individual dose requirement to achieve stable anticoagulation. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and the liver enzyme cytochrome P450 2C9 (CYP2C9) effectively account for the variability in warfarin and acenocoumarol response but are less well-defined pharmacogenetic predictors in phenprocoumon therapy. A retrospective study was performed on 185 outpatients attending anticoagulation clinics in Austria and Germany. These patients were genotyped for the VKORC1 -1639G > A and 3730G > A polymorphisms as well as for the CYP2C9 *2 and *3 polymorphisms using a reverse hybridisation-based teststrip assay. The VKORC1 -1639A allele, which was present at a frequency of 41.4% in the study cohort, significantly reduced the mean weekly phenprocoumon dose by 3 mg (19%) in the heterozygous and by 6.7 mg (43%) in the homozygous state compared to wild-type carriers (15.5 +/- 6.8 mg, p < 0.0001). A stepwise multiple regression analysis revealed that VKORC1 -1639G > A, age and CYP2C9*3 were the major independent determinants of phenprocoumon dose, accounting for 14.2, 9.1 and 4.7% of its variability, respectively (p a parts per thousand currency signaEuro parts per thousand 0.0007). The CYP2C9*2 polymorphism had a marginal influence (1.4%) and failed to reach statistical significance (p = 0.062). The VKORC1 3730G > A genotype had no additional predictive power for individual dose variability. Similar to warfarin and acenocoumarol, the VKORC1 -1639G > A polymorphism had the highest impact on the maintenance dose of phenprocoumon. The factor age was the second most important predictor and explained a greater percentage of the variability than CYP2C9 genotype.