Glutathione s-transferase polymorphisms (GSTM1, GSTP1 and GSTT1) and the risk of acute leukaemia: A systematic review and meta-analysis

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Abstract

Glutathione s-transferase (GST) polymorphisms (GSTM1, GSTP1 and GSTT1) have been considered as risk factors for developing acute leukaemia in a number of studies; however the overall results of such studies are inconsistent. To investigate a putative association of GST polymorphisms with the risk of acute leukaemia, we performed a systematic review and meta-analysis of 30 published case–control studies. To take into account the possibility of heterogeneity across the studies, a statistical test was performed. The pooled odds ratios (ORs) were assessed using both a fixed-effects and a random-effects model. The pooled OR of acute leukaemia risks associated with GSTM1 null genotype, GSTP1 Val105 allele and GSTT1 null genotype were 1.22 (95% confidence interval (CI) 1.07–1.38), 1.07 (95% CI 1.00–1.13) and 1.19 (95% CI 1.00–1.41), respectively. Significantly increased risk of acute lymphoblastic leukaemia associated with GSTM1 and GSTT1 null genotypes was observed. Their pooled ORs were 1.24 (95% CI 1.17–1.31) and 1.30 (95% CI 1.06–1.60), respectively. We also found substantial evidence of heterogeneity between the studies. Our results suggest that GSTM1 and GSTT1, but not GSTP1 polymorphisms, appear to be associated with a modest increase in the risk of acute lymphoblastic leukaemia. It is conceivable that GSTM1 and GSTT1 null genotypes may thus play a role in leukemogenesis. A review of the 30 case–control studies indicates that greater attention should be paid to the design of future studies.

Introduction

Acute leukaemia, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), is a frequent malignancy affecting both children and adults. Despite much investigation, the causes are not yet fully understood. Like many other cancers, acute leukaemia is considered to be a complex disease, which is determined by a combination of genetic and environmental factors [1], [2]. There is increasing evidence that predisposition to acute leukaemia is associated with exposure to chemicals such as benzene and chemotherapeutic agents [3], [4]. The enzymes involved in the metabolism of these carcinogens have thus received a reasonable level of attention.

Glutathione s-transferase (GST) M1, P1 and T1 are phase II enzymes that are involved in conjugation and detoxification of a wide range of xenobiotics, including environmental carcinogens and chemotherapeutic agents. GST polymorphisms have thus been considered as possible risk factors of acute leukaemia. Polymorphisms of GSTM1, GSTP1, and GSTT1 exist in all populations. The GSTM1*0 (GSTM1 null) and GSTT1*0 (GSTT1 null) alleles represent deletions of GSTM1 and GSTT1 genes and result in a loss of enzymatic activity [5]. An increased frequency of GSTM1 and GSTT1 null genotypes has been associated with a number of human malignancies [6], [7]. The 1578 A > G transition in GSTP1 gives rise to the Ile105Val polymorphism, which confers reduced enzyme activity [8].

GST polymorphisms (GSTM1, GSTP1 and GSTT1) were first reported as risk factors for acute leukaemia in 1997 [9], [10]. Since then, a number of studies have confirmed or refuted an association between GST polymorphisms and the risk of acute leukaemia [2], [4], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. These disparate findings may be due to insufficient power in some studies, differences between cancer types, type of study populations and study design. To investigate the effect of GST polymorphisms and the risk of acute leukaemia, we performed a systematic review and meta-analysis of all the available published case–control studies from January 1997 to July 2004.

Section snippets

Identification of studies

Studies published between January 1997 and July 2004 with information on GSTM1, GSTP1 or GSTT1 status and the risk of acute leukaemia were identified using two electronic databases: MEDLINE (National Library of Medicine, Washington, DC, USA) and EMBASE (Elsevier Science, New York, USA), using the search terms ‘GSTM1’ or ‘GSTP1’ or ‘GSTT1’ and ‘acute leukaemia’. Additional articles were also checked using the references cited in these publications. Articles selected for analysis were studies

Results

We identified 30 eligible studies, including nearly 12,000 subjects in relation to GST polymorphisms, which are summarised in Table 1, Table 2, Table 3. Thirteen studies were carried out in European countries, 14 in American countries and 3 in Asian countries. Hospital-based controls were used in 7 studies (Table 1). The numbers in the case–control studies varied considerably (range 45–1436 individuals). The frequencies of genotypes varied in the control participants: the frequency of GSTM1

Discussion

GST polymorphisms (GSTM1, GSTP1 and GSTT1) have been evaluated as risk factors for cancers in a number of studies. Molecular epidemiological studies indicate that individuals lacking the genes GSTM1 and GSTT1 are more likely to develop cancer than those having these genes [5]. Based upon this meta-analysis of 30 case–control studies, GSTM1 and GSTT1, but not GSTP1 polymorphisms, appear to be associated with a modest increase in the risk of acute lymphoblastic leukaemia (AML). It is conceivable

Conflict of interest statement

None declared.

Acknowledgements

We thank the anonymous reviewers for their valuable comments. We also thank Andrea Mann and Beth Ireland for proof-reading the manuscript.

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