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European Journal of Clinical Pharmacology

, Volume 66, Issue 6, pp 591–598 | Cite as

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

  • Helene Puehringer
  • Ralph M. Loreth
  • Gudrun Klose
  • Brigitte Schreyer
  • Walter Krugluger
  • Barbara Schneider
  • Christian Oberkanins
Pharmacogenetics

Abstract

Purpose

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.

Conclusion

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.

Keywords

Coumarins CYP2C9 Dose variability Phenprocoumon VKORC1 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Helene Puehringer
    • 1
  • Ralph M. Loreth
    • 2
  • Gudrun Klose
    • 2
  • Brigitte Schreyer
    • 2
  • Walter Krugluger
    • 3
    • 4
  • Barbara Schneider
    • 5
  • Christian Oberkanins
    • 1
  1. 1.ViennaLab Diagnostics GmbHViennaAustria
  2. 2.Clinical HaemostaseologyWestpfalz-Klinikum GmbHKaiserslauternGermany
  3. 3.Department of Clinical ChemistryRudolfstiftung HospitalViennaAustria
  4. 4.Department of Clinical ChemistryDonauspitalViennaAustria
  5. 5.Section for Medical Statistics and InformaticsMedical University ViennaViennaAustria

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