Evaluation of the Effect of Genetic Variations in GATA-4 on the Phenprocoumon and Acenocoumarol Maintenance Dose

Abstract

Aim: To investigate whether the phenprocoumon and acenocoumarol maintenance doses are influenced by genetic variations in GATA-4, a transcription factor of CYP2C9. Patients & methods: The influence of seven GATA-4 SNPs on the coumarin maintenance dose was investigated by performing an analysis of variance trend analysis, stratified for CYP2C9 genotypes. Results of the best-explaining SNP were validated in the Rotterdam Study cohort. Results: The largest dose differences were found for rs3735814 in patients using acenocoumarol and having the common allele for CYP2C9. The mean dosages decreased from 2.92 mg/day for the patients having the GATA-4 common alleles to 2.65 mg/day for the patients carrying one GATA-4 variant allele and to 2.37 mg/day for patients carrying two GATA-4 variant alleles (p = 0.004). Results could not be replicated in the validation cohort. For phenprocoumon, no significant effects were observed. Conclusion: Genetic variation in GATA-4 does not seem relevant for clinical implementation.

Original submitted 31 August 2012; Revision submitted 12 October 2012

KEYWORDS::

• acenocoumarol
• CYP2C9
• GATA-4
• pharmacogenetics
• phenprocoumon

Acknowledgements

The authors acknowledge the EU Seventh Framework Programme (FP7; under grant agreement HEALTH-F2-2009-223062) for supporting this project. The authors would like to thank D Verbeek (Anticoagulation Clinic Leiden), C Klopper (Anticoagulation Clinic Medial), S van der Meer and J Berbee for their support during the data collection period, and L van Hoorn for his support during data analysis.

Financial & competing interests disclosure

This work was supported by the EU FP7 (223062). The Department of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, employing authors RMF van Schie, TI Verhoef, T Schalekamp, A de Boer and AH Maitland-van der Zee, has received unrestricted research funding from The Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private–public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government and industry), the EU Innovative Medicines Initiative (IMI), EU FP7, the Dutch Medicines Evaluation Board and the Dutch Ministry of Health and industry (including GlaxoSmithKline, Pfizer and others). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the EU FP7 (223062). The Department of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, employing authors RMF van Schie, TI Verhoef, T Schalekamp, A de Boer and AH Maitland-van der Zee, has received unrestricted research funding from The Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private–public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government and industry), the EU Innovative Medicines Initiative (IMI), EU FP7, the Dutch Medicines Evaluation Board and the Dutch Ministry of Health and industry (including GlaxoSmithKline, Pfizer and others). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.