Genetic variation in GATA-4 might affect the coumarin maintenance dose

Background: It has been shown that the transcription factor GATA-4 is involved in the transcriptional regulation of CYP2C9. Therefore, it is hypothesized that genetic variations in GATA-4 play a role in the variability in coumarin dose response. Objectives: To investigate whether the phenprocoumon and acenocoumarol maintenance dose is influenced by genetic variations in GATA-4. Design: The Pre-EU-PACT database was used, which contains information about 624 phenprocoumon users and 471 acenocoumarol users. The influence of variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose was investigated by performing an ANOVA trend analysis, stratified for CYP2C9 genotypes. Results of the best explaining SNP for acenocoumarol were validated in the Rotterdam Study. This cohort study among approximately 15,000 persons was designed to investigate different diseases in a population aged over 45 years. Complete data was available for 1265 acenocoumarol users. For phenprocoumon no replication study was available. Results: Significant effects on the acenocoumarol maintenance dose were found for haplotypes GG and AG in haploblock 4 and for haplotype GG in haploblock 5&6. These effects were also observed for 3 SNPs that were part of these haplotypes. The largest dose differences were found for rs3735814 in patients being wild type for CYP2C9. The dosages decreased from 2.92 mg/day for the GATA-4 wild type patients to 2.65 mg/day for the patients carrying 1 GATA-4 variant allele to 2.37 mg/day for patients carrying 2 GATA-4 variant alleles (p=0.004). Results for rs3735814 could not be replicated in the Rotterdam Study. For phenprocoumon, no significant effects were observed. Conclusion: Genetic variations in GATA-4 appeared to influence the acenocoumarol maintenance dose in the Pre-EU-PACT study. However this could not be replicated in the Rotterdam Study. No significant association was found for phenprocoumon.