Genetic polymorphisms of glutathione-S-transferase and microsomal epoxide hydrolase in acquired aplastic anemia

ABSTRACT

Glutathione-S-transferase [GST] and microsomal epoxide hydrolase [mEh] are detoxifing enzymes that modulate the effects of exposure to various environmental cytotoxic and genotoxic agents, including those associated with increased risk of acquired aplastic anemia [AAA]. The GST mu1 [GSTM1], GST the ta1 [GSTT1] and mEh genes have polymorphisms with functional alteration that could explain the interindividual risks for AAA. To determine the frequency of GST and mEh polymorphisms as a risk factor for the susceptibility, clinical severity and response to treatment in a group of Egyptian paediatric patients with AAA. GST and mEh genotypes were determined by multiplex-PCR and PCR-RFLP analysis respectively in 21 patients with AAA and 20 healthy matched control subjects. The mEh enzyme activities genotypes were assessed. The incidence of the GSTT1 null genotype was significantly higher in AAA patients compared with the controls [85.7% vs. 50%] [OR 2.8, 95% CI 1.1-7.8, p=0.01]. The incidence of the heterozygous arginine [Arg] 139 polymorphism in exon 4 of the mEh gene was significantly higher in AAA patients compared with the controls [61.9% vs. 20%], [OR 3.07; 95% CI, 1.23-7.7, p=0.005]. The incidence of the fast mEh activity genotype was significantly higher in AAA patients compared with the controls [33.3% vs. 15%] [OR 2.9; 95% CI, 1.09-8.9, p=0.03]. Most patients with normal functional phenotype responded significantly favorably to treatment than patients with abnormal enzyme activity [p=0.027]. Genetic polymorphisms in biotransformation enzymes GSTT1-null genotype, mEh His/Arg polymorphism and fast putative functional activity could be considered as risk factors to develop AAA. Moreover, abnormal functional activity of mEh enzyme was associated with worse prognosis of the disease