Correlation of Genetic Polymorphisms of Glutathione S-Transferase and Acute Leukemia Development in Palestine رسالة ماجستير

Abstract

Glutathione S-Transferase (GST), is a primary superfamily of phase II drug-metabolizing enzymes that catalyze the conjugation of large number of xenobiotic compounds, which include environmental carcinogens. Additionally, these enzymes play an essential role in the metabolism of drugs including chemotherapeutic drugs and their metabolites. The presence of polymorphism within these transferases will reduce the body‟s ability to detoxify carcinogenic agents, thus increasing susceptibility to leukemia. Objectives: The aim of this study was to determine the association between genetic polymorphisms of Glutathione S-Transferase and acute myeloid leukemia (AML) development among Palestinian patients. Methodology: This study was carried out on thirty-six AML patients from different medical facilities in the West Bank [An- Najah National University Hospital (Nablus), Istishari Arab Hospital (Ramallah), and Augusta Victoria Hospital (Jerusalem)], and 72 healthy volunteers. Blood samples were collected in EDTA tubes for all patients and healthy volunteers. DNA was extracted from all EDTA blood samples. The two polymorphisms GSTM1 (NC_000001.10: g. [0]), and GSTT1 (NC_000022.10: g. [0]) were genotyped by using the conventional allele-specific polymerase chain reaction (PCR), while the third polymorphism GSTP1 (NM_000852.4: c.313A>G) was genotyped by restriction fragment length polymorphism (RFLP). Sanger sequencing was conducted to confirm the PCR-RFLP results. VI Results: The null genotypes of GSTM1 showed no association with AML [OR 1.50 (0.62–3.59); P = 0.362]. The presence of GSTP1 (NM_000852.4: c.313A>G) polymorphism showed no association with AML [OR= 0.59 (CI: 0.26–1.36); P = 0.218]. In contrast, the null genotypes of GSTT1 showed a significant association with AML [OR = 2.40 (CI: 1.03–5.59); P = 0.04]. Further, a haplotype analysis between AML cases and controls showed a positive association (P < 0.05). It was found that the subjects carrying (GSTT1 present/GSTP1 heterozygous Ile/Val) genotype [OR= 0.35 (CI: 0.13–0.96); P = 0.037], or carrying (GSTT1 present/GSTM1 present/GSTP1 heterozygous Ile/Val) genotype [OR= 2.67 (CI: 0.08–0.84); P = 0.018] had a protective effect from developing AML. Conclusion: In conclusion, there was a statistically significant association between the deletion of the GSTT1 gene with increased risk of AML. On the other hand, the haplotype analysis showed that the combination of (GSTT1present/GSTP1 heterozygous Ile/Val) genotypes played a protective role in developing AML. This protection increases in the presence of (GSTT1 present/GSTM1 present/ GSTP1 heterozygous Ile/Val).