GSTM1 and GSTT1 Null Polymorphisms and Childhood Acute Leukemia Risk: Evidence from 26 Case-Control Studies

Qiuqin Tang,Simin Zhang,Chuncheng Lu,Lingqing Hu,Wei Wu,Jing Li,Beilei Yuan,Daozhen Chen,Xinru Wang,Hongjuan Ding,Hong Sun,Jiahao Sha,Di Wu,Yankai Xia,Michael Scheurer

doi:10.1371/journal.pone.0078810

Abstract

Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) null polymorphisms and childhood acute leukemia; however, the conclusions remain controversial. We performed an extensive meta-analysis on 26 published case-control studies with a total of 3252 cases and 5024 controls. Crude odds ratios (ORs) with 95% confidence interval were used to assess the strength of association between childhood acute leukemia risk and polymorphisms of GSTM1 and GSTT1. With respect to GSTM1 polymorphism, significantly increased risk of childhood acute leukemia was observed in the overall analysis (OR = 1.30; 95%CI, 1.11-1.51). Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism are associated with childhood acute leukemia in group of Asians (OR = 1.94; 95%CI, 1.53-2.46), Blacks (OR = 1.76; 95%CI, 1.07-2.91), ALL (OR = 1.33; 95%CI, 1.13-1.58), ‘< 100 cases and <100 controls’ (OR = 1.79; 95%CI, 1.21-2.64), ‘≥ 100 cases and ≥ 100 controls’ (OR = 1.25; 95%CI, 1.02-1.52), and population-based control source (OR = 1.40; 95%CI, 1.15-1.69). With respect to GSTT1 polymorphism, significant association with childhood acute leukemia risk was only found in subgroup of Asian. This meta-analysis supports that GSTM1 null polymorphism is capable of causing childhood acute leukemia susceptibility.

Highlights

Leukemia is the most common form of cancer in childhood accounting for approximately one third of all childhood cancers [1]; which is a heterogeneous disease lacking a high penetrant germ line-inherited predisposition, except for rare cases with genetic instability or immunodeficiency syndromes
In the stratified analyses of glutathione Stransferase mu-1 (GSTM1) null polymorphism, we found a significant influence on childhood acute leukemia risks in Asian and Black ethnic groups, ALL and population-based controls
The association of the GSTM1 null polymorphism but not the glutathione S-transferase theta-1 (GSTT1) polymorphism with childhood acute leukemia may be an indication of substrate specificity of GSTM1 in metabolism of agents that are involved in the etiology of childhood acute leukemia

Summary

Introduction

Leukemia is the most common form of cancer in childhood accounting for approximately one third of all childhood cancers [1]; which is a heterogeneous disease lacking a high penetrant germ line-inherited predisposition, except for rare cases with genetic instability or immunodeficiency syndromes. Molecular epidemiologic case-control studies suggest that children harboring null genotype of the glutathione Stransferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genes might have an increased risk of the development of childhood acute leukemia. The mu class of GSTs, encoded by the GSTM1 gene, is found on the chromosome 1p13.3 [5]. The theta class of GSTs, encoded by the GSTT1 gene, is locate on the chromosome 22q11.23 [6]. An increased frequency of GSTM1 and GSTT1 null genotypes has been associated with several types of malignancies, including stomach cancer [10], lung cancer [11], pituitary adenomas [12], bladder cancer [13], prostate cancer [14], cervical cancer [15], and acute leukemia [16]

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