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

  • Pharmacogenetics
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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.

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Authors and Affiliations

  1. ViennaLab Diagnostics GmbH, Gaudenzdorfer Guertel 43-45, 1120, Vienna, Austria

    Helene Puehringer & Christian Oberkanins

  2. Clinical Haemostaseology, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany

    Ralph M. Loreth, Gudrun Klose & Brigitte Schreyer

  3. Department of Clinical Chemistry, Rudolfstiftung Hospital, Vienna, Austria

    Walter Krugluger

  4. Department of Clinical Chemistry, Donauspital, Vienna, Austria

    Walter Krugluger

  5. Section for Medical Statistics and Informatics, Medical University Vienna, Vienna, Austria

    Barbara Schneider

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  1. Helene Puehringer
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  2. Ralph M. Loreth
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  3. Gudrun Klose
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  7. Christian Oberkanins
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Correspondence to Helene Puehringer.

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Puehringer, H., Loreth, R.M., Klose, G. et al. VKORC1 −1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement. Eur J Clin Pharmacol 66, 591–598 (2010). https://doi.org/10.1007/s00228-010-0809-2

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  • DOI: https://doi.org/10.1007/s00228-010-0809-2

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