title: VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 </= 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ViennaLab Diagnostics GmbH, Gaudenzdorfer Guertel 43-45, 1120, Vienna, Austria. puehringer@viennalab.co.at
authors.forename: Helene
authors.initials: H
authors.lastname: Puehringer
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Loreth
authors.forename: Gudrun
authors.initials: G
authors.lastname: Klose
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schreyer
authors.forename: Walter
authors.initials: W
authors.lastname: Krugluger
authors.forename: Barbara
authors.initials: B
authors.lastname: Schneider
authors.forename: Christian
authors.initials: C
authors.lastname: Oberkanins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001317:Austria; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005858:Germany; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010644:Phenprocoumon / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases; D044465:White People / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D010644:Phenprocoumon