Variations in glutathione‐S‐transferase genes influence risk of chronic myeloid leukemia

Abstract

Glutathione S-transferases (GSTs) are phase II enzymes that detoxify hazardous xenobiotics including carcinogens. Inter-individual variations in GSTM1 and GSTT1 loci have been associated with several types of cancer, including leukemias. In this study, we investigated the possible association between GSTM1 and GSTT1 polymorphisms and susceptibility to chronic myeloid leukemia (CML) in a Turkish population. In a case-control study, 106 CML patients and 190 healthy controls were evaluated for GSTM1 and GSTT1 polymorphisms. GSTM1 null (GSTM1(-)) genotype frequencies in CML cases and controls were 45.3% and 42.6%, respectively. GSTT1 null (GSTT1(-)) genotype frequencies were 44.3% and 18.4%, respectively. The frequency of the GSTT1(-) genotype among CML patients was significantly higher than in controls [odds ratio (OR) 3.53, 95% confidence interval (CI) 2.08-6.00; P < 0.0001]. Individuals with the GSTM1(-) genotype did not have increased risk of CML [OR: 1.11; 95% CI: 0.69-1.80; P = 0.714]. The combined GSTM1(-)/GSTT1(-) genotype was significantly associated with risk of CML compared to the GSTM1(+) /GSTT1(+) genotype which was most frequent in both cases and controls [OR: 9.47; 95% CI: 3.61-24.87]. Similar findings have only been obtained in Turkish and Indian populations but not elsewhere. The GSTM1(+) /GSTT1(-) genotype was associated with a 2.5-fold increased risk compared with the GSTM1(-)/GSTT1(+) genotype, the second most frequent genotype (OR; 2.46; 95% CI: 1.17, 5.20), suggesting a complex interaction between GSTM1 and GSTT1. Our results indicate an association between the GSTT1(-) genotype, either alone or in combination with GSTM1(-) genotype, and risk of CML, suggesting a possible interaction between GSTM1 and GSTT1. These findings, which are possibly restricted to Turkey and India, warrant further research.

Influence of glutathione S‐transferases (GSTM1, GSTT1, and GSTP1) genetic polymorphisms and smoking on susceptibility risk of chronic myeloid leukemia and treatment response

“…In this study, no association was found between CML risk and GSTT1 polymorphism, consistent with Weich et al () report, this finding may be due to low frequency of individuals carrying the GSTT1‐null genotype or indicating a protective effect of GSTT1/null on CML risk. Contrary to our data, several studies have described increased risk of CML associated with the GSTT1/null genotype in different ethnicities (Özten et al, ; Taspinar et al, ). In the current study, we analyzed the relationship between dual combinations of gene–gene and gene–environment interactions using ORs as estimated effect in CML risk.…”

“…In the current study, a significant increase of 6.51‐, 3.17‐, and 4.40‐fold in the probability of having CML in individual who were both smokers and carried GSTM1/null, GSTT1/null and GSTP1M*genotypes, respectively, was indicated. Not many studies have evaluated gene–smoking interaction concerning CML risk to date, except, a recent study that did not find no significant association for susceptibility genotypes to CML risk when smoking was considered (Özten et al, ). In some studies CML risk has been associated with chemical exposures in the shoe‐making industry or benzene in Turkey (Yaris, Dikici, Akbulut, Yaris, & Sabuncu, ).…”

“…A multiplex PCR was used for GSTT1 (NM_000853.3) and GSTM1 (NG_009246.1) amplification with β‐globin gene as an internal positive control. The primers used were described in Özten et al, . The absence of PCR products for GSTM1 and GSTT1 (219 and 480 bp respectively) in the presence of β‐globin PCR product (268bp) indicated the null genotype for each.…”

“…Earlier association studies have identified the roles of polymorphic variants in different crucial genes associated with predisposing individuals to CML, with incompatible results (Bruzzoni-Giovanelli et al, 2015;He et al, 2014). These incompatibilities may be due to lifestyle factors, ethnic differences, environmental exposures in population cohorts studied (Davies et al, 2014;Özten, Sunguroğlu, & Bosland, 2012). Glutathione S-transferase (GST) genes, an important family of phase II metabolizing enzymes, catalyze the conjugation of a large spectrum of endogenous and exogenous compounds, including carcinogens, anticancer drugs, and their metabolites with reduced glutathione, thus enabling their detoxification and elimination (Hayes, Flanagan, & Jowsey, 2005).…”

“…It has been suggested that individual inherited genetic differences in the ability to metabolize carcinogens correlated with polymorphism in detoxification enzymes may influence in carcinogen metabolism and cancer susceptibility (Taspinar et al, 2008;Yaya et al, 2014). Whole-gene deletion polymorphisms of GSTM1 (OMIM accession number: *138350) and GSTT1 (OMIM accession number:*600436) genes and the single nucleotide polymorphism (SNP) in GSTP1 c. 313 A>G ( p. 105Ile>Val; rs1695) (OMIM accession number:*134660) lead to the absence or decreased detoxification ability of enzymes, their dysfunction, and finally may impact on the risk of cancer development, heterogeneous drug responsiveness (Davies et al, 2014;Hollman, Tchounwou, & Huang, 2016;Özten et al, 2012). Several studies determined only the role of GST polymorphisms on CML susceptibility (Al-Achkar, Azeiz, Moassass, & Wafa, 2014;He et al, 2014;Özten et al, 2012) and some studies assessed their impact on treatment response (Davies et al, 2014;Kassogue et al, 2014).…”