Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves

Abstract

Interindividual variability in stable warfarin doses is largely attributed to VKORC1 and CYP2C9 variants. On the basis of a recent finding of the role of GATA4 in control of CYP2C9 expression, we tested a possible effect of GATA4 genotypes on variability in warfarin response using 201 Korean patients with prosthetic cardiac valves. Two single-nucleotide polymorphisms (SNPs), rs2645400 (G>T) and rs4841588 (G>T), were significantly associated with stable warfarin doses in patients carrying CYP2C9 wild-type homozygotes; homozygote carriers of these two SNPs required higher doses than those with other genotypes (5.94±1.73 versus 5.34±1.88 mg, P=0.026; 5.94±1.66 versus 5.37±1.92, P=0.036, respectively). Multivariate analysis showed that two GATA4 combinations, rs867858 (G>T)/rs10090884 (A>C) and rs2645400 (G>T)/rs4841588 (G>T), increased contribution to the overall warfarin dose variability from 36.4 to 40.9%. This study revealed that GATA4 can be predictive of stable warfarin dose and extended warfarin pharmacogenetics further to the regulation of CYP2C9 expression.

Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

“…However, the results of the present study did not corroborate an association between other NRs GATA4, ESR1, NR1I2, and HNF4α polymorphisms and warfarin dose, suggested by Moon et al [12,13] and Jeong et al [14]. Indeed, in three separate research studies performed on a single population of 201 Korean patients with prosthetic cardiac valve, they found that GATA4 variants rs2645400 and rs4841588, rs2472682 in the NR1I2, and the combination of rs2501873 in the ESR1 and rs3212198 in the HNF4A, were marginally associated with warfarin dose requirements.…”

“…We have also considered the association of the three VDR variants with stable warfarin dose requirements at 3 months by excluding CYP2C9 and VKORC1 activity status from the list of adjustment variables. Results show that associations are strongly maintained with rs11168292 (Beta (SE) = 0.083 (0.022); P = 1.26 × 10 We have also tested for the allelic association of four out of five additional SNPs that have been previously reported in the literature [12][13][14] for association with warfarin dose (Table 3). No significant association was detected between warfarin dose requirements and rs2501873 in the ESR1 (P = 0.486), rs2472682 in the NR1I2 (0.868), rs2645400 (P = 0.144), and rs4841588 (P = 0.402) in GATA4.…”

“…The influence of genetic variants in NR genes on the warfarin dose requirement has only been investigated in a limited number of studies so far [12][13][14] and the pharmacogenetic effects attributable to specific NRs polymorphisms have not been comprehensively explored. In light of the possible impact of the disruption of the CYP2C9 gene expression via NR on CYP2C9 enzyme activity we here aim to investigate the association of NR polymorphisms on warfarin dosing requirements.…”

SNP Analysis, Genome Wide Association Studies and Pharmacogenetic implications of Acute Myocardial Infarction

“…[25] Warfarin is an anti-coagulant and is used as a preventive for the formation of blood clots in blood vessels and their migration. [26] For the gene ESR1, the SNP variant associations of rs9340799 and rs4870061, and rs1801132 and rs2234693 were found to influence the drug therapy of prescribed drugs Letrozole, Raloxifene, Tamoxifen, Atorvastatin, and Anastrozole.…”

Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves

“…Several studies revealed that GGCX gene polymorphisms in Asian populations could be a factor on warfarin dose requirements [7,8]. Recently, our study group showed that polymorphism of GATA4, a transcription factor of CYP2C9, was marginally associated with warfarin responses [9]. Nevertheless, a large part of variability in the warfarin dose requirements remains unexplained.…”