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VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement.
Eur J Clin Pharmacol. 2010 Jun; 66(6):591-8.EJ

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.

Authors+Show Affiliations

ViennaLab Diagnostics GmbH, Gaudenzdorfer Guertel 43-45, 1120, Vienna, Austria. puehringer@viennalab.co.atNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20376629

Citation

Puehringer, Helene, et al. "VKORC1 -1639G>A and CYP2C9*3 Are the Major Genetic Predictors of Phenprocoumon Dose Requirement." European Journal of Clinical Pharmacology, vol. 66, no. 6, 2010, pp. 591-8.
Puehringer H, Loreth RM, Klose G, et al. VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement. Eur J Clin Pharmacol. 2010;66(6):591-8.
Puehringer, H., Loreth, R. M., Klose, G., Schreyer, B., Krugluger, W., Schneider, B., & Oberkanins, C. (2010). VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement. European Journal of Clinical Pharmacology, 66(6), 591-8. https://doi.org/10.1007/s00228-010-0809-2
Puehringer H, et al. VKORC1 -1639G>A and CYP2C9*3 Are the Major Genetic Predictors of Phenprocoumon Dose Requirement. Eur J Clin Pharmacol. 2010;66(6):591-8. PubMed PMID: 20376629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VKORC1 -1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement. AU - Puehringer,Helene, AU - Loreth,Ralph M, AU - Klose,Gudrun, AU - Schreyer,Brigitte, AU - Krugluger,Walter, AU - Schneider,Barbara, AU - Oberkanins,Christian, Y1 - 2010/04/08/ PY - 2009/11/27/received PY - 2010/02/24/accepted PY - 2010/4/9/entrez PY - 2010/4/9/pubmed PY - 2010/7/27/medline SP - 591 EP - 8 JF - European journal of clinical pharmacology JO - Eur. J. Clin. Pharmacol. VL - 66 IS - 6 N2 - 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. SN - 1432-1041 UR - https://www.unboundmedicine.com/medline/citation/20376629/VKORC1__1639G>A_and_CYP2C9_3_are_the_major_genetic_predictors_of_phenprocoumon_dose_requirement_ L2 - https://dx.doi.org/10.1007/s00228-010-0809-2 DB - PRIME DP - Unbound Medicine ER -