The effect of polymorphisms of gamma-glutamyl hydrolase (GGH) gene on methotrexate-induced toxicity in acute lymphoblastic leukemia

Abstract

Context: Acute lymphoblastic leukemia patients show differences in methotrexate-induced toxicity after treatment with this anti-cancer drug. Pharmacogenetics is an important determining factor for toxicity diversity. Objective: In this study, the effect of +452 CT and ? 401CT polymorphisms of Gamma-glutamyl hydrolase (GGH) gene on methotrexate serum levels and its associated toxicity in patients with acute lymphoblastic leukemia was assessed. Furthermore, the frequency of the above polymorphisms was investigated for the first time in Iran. Material and methods: The prevalence of these polymorphisms was assessed in 83 Iranian patients with ALL using PCR and RFLP. The relationship between the polymorphism and serum methotrexate levels and its toxicity was estimated by calculating the Odds Ratio. Results: No correlation was found between +452CT polymorphism and serum levels of methotrexate and methotrexate-related toxicity. ?401CT polymorphism was found to be correlated with methotrexate-related toxicity leading to thrombocytopenia (95% CI=0.009-0.019, odds ratio=0.265) and leukopenia (95% CI=0.021-0.042, odds ratio=2.182) in consolidation phase of the treatment. Discussion: C allele polymorphism of -401C/T allele is a risk factor of leukopenia and thrombocytopenia in patients treated with methotrexate. Moreover, our results suggested that the T allele had a supporting role in prevention of thrombocytopenia. Conclusion: Evaluation of patients for methotrexate-related polymorphism of GGH gene may be useful to determine the appropriate dose of methotrexate and reducing its toxic side effects.