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Role of CYP4F2, CYP2C19, and CYP1A2 polymorphisms on acenocoumarol pharmacogenomic algorithm accuracy improvement in the Greek population: need for sub-phenotype analysis

  • Georgia Ragia EMAIL logo , Ioanna-Maria Karantza , Eleni Kelli-Kota , Vana Kolovou , Genovefa Kolovou , Stavros Konstantinides , Efstratios Maltezos , Anna Tavridou , Dimitrios Tziakas , Anke H. Maitland-van der Zee and Vangelis G. Manolopoulos
Published/Copyright: December 19, 2017
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Drug Metabolism and Personalized Therapy
From the journal Drug Metabolism and Personalized Therapy Volume 32 Issue 4

Abstract

Background:

We have earlier developed a pharmacogenomic algorithm for acenocoumarol dose prediction in Greek patients that included CYP2C9/VKORC1 genetic information. This study aims at analyzing the potential effect of CYP4F2, CYP2C19, and CYP1A2 gene polymorphisms on acenocoumarol dose requirements and at further improving the Greek-specific pharmacogenomic algorithm.

Methods:

A total of 205 Greek patients taking acenocoumarol (140 who reached and 65 who did not reach stable dose), participants of acenocoumarol EU-PACT trial, were included in the study. CYP4F2, CYP2C19, and CYP1A2 polymorphisms were genotyped by use of the PCR-RFLP method. All patients were previously genotyped for CYP2C9/VKORC1 polymorphisms.

Results:

In the pooled sample, CYP4F2, CYP2C19, and CYP1A2 polymorphisms do not affect independently acenocoumarol dose requirements. For CYP4F2, significant effects were found on patients’ ability to reach stable dose and on acenocoumarol dose requirements when CYP2C9/VKORC1 sub-phenotypes were analyzed. Specifically, when the patients were stratified according to their CYP2C9/VKORC1 functional bins, in sensitive responders, CYP4F2*3 allele carriers (CYP4F2 *1/*3 and *3/*3 genotypes) were more frequent in the patient group who reached stable dose (p=0.049). Additionally, in CYP2C9 intermediate metabolizers (IMs), after adjusting for age, weight, and VKORC1 genotypes, CYP4F2 genotypes were significantly associated with acenocoumarol stable dose (β: 0.07; 95% CI: 0.006–0.134; p=0.033).

Conclusions:

CYP4F2 gene shows a prominent weak association with acenocoumarol dose requirements. Sub-phenotype analysis is potentially important in determining additional gene polymorphisms that are associated with acenocoumarol dose requirements.

Keywords: acenocoumarol; dosing algorithm; Greece; pharmacogenomics; CYP4F2; CYP2C19; CYP1A2; CYP2C9; EU-PACT; VKORC1

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the European Commission Seventh Framework Program (10.13039/100011272, HEALTH-F2-2009-223062).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: Georgia Ragia is an employee at DNALEX S.A. Genovefa Kolovou has given talks, attended conferences and participated in trials sponsored by MSD, Amgen, Sanofi, Angelini, Aegerion. Anke H. Maitland-van der Zee received an unrestricted research grant from GSK and participated in an advisory board for Astra Zeneca.

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Received: 2017-11-7
Accepted: 2017-11-15
Published Online: 2017-12-19
Published in Print: 2017-12-20

©2017 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Creation of the Swiss group of Pharmacogenomics and personalised Therapy (SPT)
  4. Publisher’s Note
  5. Swarup A.V. Shah won the poster award at the 4th Annual Conference of ESPT
  6. Original Articles
  7. COQ2 polymorphisms are not associated with increased risk of statin-induced myalgia/myopathy in the Czech population
  8. Role of CYP4F2, CYP2C19, and CYP1A2 polymorphisms on acenocoumarol pharmacogenomic algorithm accuracy improvement in the Greek population: need for sub-phenotype analysis
  9. Estimation of fractions metabolized by hepatic CYP enzymes using a concept of inter-system extrapolation factors (ISEFs) – a comparison with the chemical inhibition method
  10. In vitro modulation of the cytochrome P450 and ABCB1/P-glycoprotein activities of the aqueous extract of Allophylus cominia (L) Sw. leaves
  11. Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer
  12. Drug-drug interactions in cancer chemotherapy: an observational study in a tertiary health care centre
  13. Acknowledgment
https://doi.org/10.1515/dmpt-2017-0034
Keywords for this article
acenocoumarol; dosing algorithm; Greece; pharmacogenomics; CYP4F2; CYP2C19; CYP1A2; CYP2C9; EU-PACT; VKORC1

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Creation of the Swiss group of Pharmacogenomics and personalised Therapy (SPT)
  4. Publisher’s Note
  5. Swarup A.V. Shah won the poster award at the 4th Annual Conference of ESPT
  6. Original Articles
  7. COQ2 polymorphisms are not associated with increased risk of statin-induced myalgia/myopathy in the Czech population
  8. Role of CYP4F2, CYP2C19, and CYP1A2 polymorphisms on acenocoumarol pharmacogenomic algorithm accuracy improvement in the Greek population: need for sub-phenotype analysis
  9. Estimation of fractions metabolized by hepatic CYP enzymes using a concept of inter-system extrapolation factors (ISEFs) – a comparison with the chemical inhibition method
  10. In vitro modulation of the cytochrome P450 and ABCB1/P-glycoprotein activities of the aqueous extract of Allophylus cominia (L) Sw. leaves
  11. Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer
  12. Drug-drug interactions in cancer chemotherapy: an observational study in a tertiary health care centre
  13. Acknowledgment
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