Document 3V55ZKK5nwObg6B7Y3MJnjyO
IJC
International Journal of Cancer
GSTT1 and GSTM1 polymorphisms and myelodysplastic syndrome risk: a systematic review and meta-analysis
Issa J. Dahabreh1, Stavroula Giannouli2, Vaia Gota3 and Michael Voulgarelis4
1 Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA 2 Department of Hematology, Medical School, National University of Athens, Athens, Greece 3 Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece 4 Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece
Glutathione-S-transferace polymorphisms may make hematopoietic lineage cells susceptible to genotoxicity following exposure to heavy metals or benzene. We conducted a systematic review and meta-analysis to define the effect of GSTM1 and GSTT1 null polymorphisms on MDS risk. We searched the PubMed and SCOPUS databases to identify peer-reviewed published case-control studies investigating the association between GSTT1 and/or GSTM1 null genotypes and development of MDS. Between-study heterogeneity was assessed using Cochran's Q statistic and the I2 statistic. Odds ratios from individual studies were pooled using fixed and random effects models. Thirteen studies were considered eligible for the GSTT1 metaanalysis (1471 cases, 1907 controls) and 10 were considered eligible for the GSTM1 meta-analysis (1161 cases, 1668 controls). For the GSTT1 polymorphism, there was moderate between study heterogeneity (pQ 5 0.01; I2 5 52.3%) and the null genotype was significantly associated with increased risk of MDS development, random effects OR 5 1.43 (95% CI, 1.09 1.89); p 5 0.01. For the GSTM1 polymorphisms there was moderate between-study heterogeneity (p 5 0.07; I2 5 43.1%) and the random effects OR 5 1.02 (95% CI, 0.821.28) was non-significant (p 5 0.85). The GSTT1 null genotype is a significant risk factor for MDS development. Gene-environment interactions need to be further explored.
The myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by ineffective hematopoiesis, bone marrow dysplastic changes and an increased risk of transformation to acute leukemia. The generally accepted mechanism of primary MDS pathogenesis involves an initial deleterious genetic event within a hematopoietic stem cell, subsequent development of an excessive cytokine/inflammatory response leading to a pro-apoptotic/proliferative state, and resultant peripheral cytopenias despite the presence of a hypercellular bone marrow. The presence of detectable cytogenetic abnormalities in approximately 4070% of patients with primary MDS and over 80% of those with secondary MDS, as well as
Key words: glutathione-S-transferace, GSTT1, GSTM1, myelodysplastic syndrome, meta-analysis Abbreviations: FAB: French-American-British; MDS: myelodysplastic syndrome; OR: odds ratio; RA/RARS: refractory anemia/refractory anemia with an excess of blasts; RAEB/RAEB-t: refractory anemia with an excess of blasts/refractory anemia with an excess of blasts in transformation; WHO: World Health Organization DOI: 10.1002/ijc.24940 History: Received 28 Jul 2009; Accepted 10 Sep 2009; Online 8 Oct 2009 Correspondence to: Michael Voulgarelis, Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias St., 11527 Athens, Greece, Tel: 30 210 7462648, Fax: 30 210 7462664, E-mail: mvoulgar@med.uoa.gr
the validated prognostic value of cytogenetic data have been considered to support the theory of an inciting genetic event.1
Recent studies, have demonstrated that the recurrent cytogenetic abnormalities associated with MDS, previously considered the ``primary'' cause of disease, are actually ``secondary'' events that arise due to cytogenetically cryptic initiating lesions in an established clonal hematopoietic stem cell population.2 Such initiating events are likely to be heterogeneous and could either be inherited or result from acquired DNA damage, genomic instability, defective DNA repair, or perturbations in cellular signaling pathways that give rise to stem cell clones with a proliferative or survival advantage. While genetic and familial mapping studies have clearly demonstrated that inherited mutations in specific genes, such as AML1, NF1, or genes mediating DNA repair, can predispose to the acquisition of secondary cytogenetic abnormalities and MDS, it is likely that highly penetrant inherited mutations will account for only a minority of MDS cases.35 Furthermore, the majority of MDS cases are ``sporadic'' and several epidemiologic investigations have demonstrated associations between MDS and exposure to a variety of environmental toxins.6 In light of these findings, a complex MDS pathogenetic model has been proposed, whereby genetic predisposition to the disease, mediated by low penetrance polymorphisms in DNA repair genes, cooperates with environmental carcinogens.7,8
Among the most extensively studied inherited genetic risk factors for MDS are variants of glutathione S-transferases (GSTs, Enzyme Commission (EC) number 2.5.1.18). Among the GST substrates, there are several environmental
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carcinogens found in food, air, or medications, such as polycyclic aromatic hydrocarbons, found in combustion products, diet, and tobacco smoke. Polycyclic aromatic hydrocarbons are activated by members of the phase 1 cytochrome P-450 supergene family to epoxide-containing metabolites (e.g., benzo[a]pyrene-7,8-diol-9,10-oxide), which are substrates for the mu, alpha, theta and pi GST classes.9 GSTT1 and GSTM1 are good candidate cancer susceptibility genes because of their involvement in the metabolism of chemicals such as methylating agents, pesticides, and industrial solvents. In vitro studies suggest that both GSTT1 and GSTM1 enzymes protect cells from the toxic products of phase 1 detoxification reactions.10 However, GSTT1-catalyzed reactions can also increase the toxicity of some compounds, such as dichloromethane. GSTs also conjugate isothiocyanates, which are potent inducers of enzymes that detoxify environmental mutagens. The conjugation process diverts the isothiocyanates from the enzyme induction pathway into excretion, leading to elimination of these anticarcinogenic substances and thus decreasing their potential chemopreventive effect. The pleotropy of GST enzyme functions indicates that their role in human carcinogenesis is complex.
The most common polymorphism in GSTT1 consists of a deletion of the whole gene (null genotype), resulting in the lack of active enzyme.11,12 Complete deletion at the GSTT1 locus was hypothesized by observing the phenotypic variation in glutathione-related detoxification of halomethanes by human erythrocytes, resulting in ``conjugator'' and ``nonconjugator'' phenotypes. Individuals with homozygous deletions of either the GSTM1 locus or the GSTT1 locus have no enzymatic functional activity of the respective enzyme. This has been confirmed by phenotype assays that have demonstrated 94% or greater concordance between phenotype and genotype. Many genotoxins, including benzene and cytotoxic drugs, act directly in vivo on bone marrow cells.13 Bone marrow cell protection from these insults depends upon intact detoxification pathways and DNA repair systems to prevent cellular mutagenesis/apoptosis.14 Exposure to environmental toxins, such as benzene or heavy metals, has been implicated in the etiology of MDS.15 Therefore, it has been proposed that the decreased production of GSTM1 and GSTT1, characteristic of the null genotypes, may be associated with an increased MDS risk in the presence of environmental mutagens and/or carcinogens exposure.
Individual genetic association studies, such as those that have evaluated selected GST polymorphisms and risk of MDS, are frequently extremely underpowered and often report small or variable effects. We therefore conducted a systematic review and meta-analysis to more accurately define the effect of GSTM1 and GSTT1 polymorphisms on risk for MDS.
Material and Methods
Study identification, eligibility criteria, and data extraction We used the PubMed (MEDLINE) and SCOPUS databases to identify genetic association studies published before April
30th, 2009, investigating the association between the GSTT1 and/or GSTM1 null genotypes and MDS. We also used the National Institutes of Health (NIH) Genetic Association Database (GAD, last search: April 30th, 2009). Computer searches were conducted using keywords relevant the genes of interest (e.g., ``GSTT1,'' ``GSTM1'' and ``glutathione Stransferase'') in combination with words related to ``myelodysplastic syndrome'' and ``myelodysplasia.'' To increase the yield of our search, we also scanned the reference lists of all relevant studies and review articles, manually searched relevant journals and consulted with experts in the field of MDS. Casecontrol studies that employed validated genotyping methods and examined the prevalence of GSTT1 and/or GSTM1null genotypes were eligible for inclusion. Family based studies were excluded owing to different design considerations. The search was limited to studies published in English.
The following information was abstracted from each study: first author, journal, year of publication, study design, matching, geographical location, ethnicity of participants, definition and numbers of cases and controls, source of controls, DNA extraction and genotyping methods, frequency of GST null and normal genotypes, MDS classification criteria (French-American-British, FAB or World Health Organization, WHO), morphological classification (refractory anemia with or without ringed sideroblasts, RA/RARS; refractory anemia with an excess of blasts, RAEB; refractory anemia with an excess of blasts in transformation, RAEB-t).
Evidence synthesis For GSTM1 and GSTT1, since only two genotypes are possible, we compared genotype frequencies (null versus normal) between cases and controls. All associations were presented as odds ratios (OR) with the corresponding 95% confidence interval (CI). Between-study heterogeneity was assessed using Cochran's Q statistic and inconsistency quantified using the I2 statistic, which describes the proportion of variation in the log odds ratios that is attributable to genuine differences across studies rather than to random error.16 Pooled OR was estimated based on the individual OR using fixed- (MantelHaenszel) and random-effects (DerSimonian and Laird) models.1720 Cumulative meta-analysis was carried out for each polymorphism to evaluate the trend of random effects OR over time.21,22
Assessment of bias and subgroup analysis Source of controls (e.g., population versus hospital based) and ethnicity (individuals of East Asian origin versus all other) were pre-specified as characteristics for assessment of heterogeneity by subgroup analysis. The differential magnitude of effects in large versus small studies was assessed using the Egger and Begg tests.23,24 A test for interaction was used to compare the OR of the first study with the pooled OR of subsequent studies, as well as the pooled ORs between subgroups.25 The following subgroup comparisons were prespecified: source of controls (healthy versus hospital), MDS
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Table 1. Characteristics of studies included in the meta-analysis
Study, Year
Ethnicity
Secondary MDS MDS cases (n, %)
MDS classification
Chen, 1996
Caucasian 90
NR
FAB
Atoyebi, 1997 NR
166 NR
NR
Basu, 1997
NR
57 NR
NR
Okada, 1997
Preudhomme, 1997
Sasai, 1999
Davies, 2000
East Asian 59 Caucasian 174
East Asian 116 Causasian 13
Tsabouri, 2000 Caucasian 54
NR 16 (9.2%)
NR FAB
0 FAB 0 FAB
0 FAB
Arruda, 2001 NR
49 0
FAB
Haase, 2002 NR
128
Varkonyi, 2008 Caucasian 86
14 (10.9%) FAB 0 WHO
Stavropoulou, 2008
Fabiani, 2009
Caucasian Caucasian
323 for GSTT1; 302 for GSTM1
156 for GSTT1; 157 for GSTM1
0 0
FAB WHO
Controls 190 for GSTT1; 201 for GSTM1 112
100
50 100
43 153
60
276
239 99
330
155
Source of controls
Cancer free patients attending urology clinics
Laboratory staff and general medical outpatients
Laboratory staff, general medical patients, women attending the antenatal clinic
NR
Blood donors
Healthy volunteers
Blood donors participants in an epidemiological study
Cancer-free patients from the internal medicine department, malignant and hematological disease patients were excluded
Newborns from the same university hospital as controls
Healthy individuals
Hospitalized patients from the same university hospital
Healthy donors
Individuals with no history of previous malignancies and normal peripheral blood counts
Matching No
No
No
No No No No
Age, smoking, sex
No
No Age, sex
Age, sex
Age, sex
Genotyping method Multiplex PCR PCR PCR
PCR Multiplex PCR Multiplex PCR Multiplex PCR Multiplex PCR
Multiplex PCR Multiplex PCR Multiplex PCR Multiplex PCR
Multiplex PCR
GSTT1 null cases (n, %) 41 (45.6) 35 (21.1) 16 (28.1)
27 (45.8) 39 (22.4) 62 (53.4)
2 (15.4) 6 (11.1)
7 (14.3) 28 (21.9) 17 (19.8) 58 (18.0)
38 (24.4)
GSTT1 null controls (n, %) 30 (15.8)
18 (16.1)
23 (23)
23 (46) 19 (19) 13 (30.2) 23 (15.0)
4 (6.7)
44 (15.9)
38 (15.9) 25 (25.3)
52 (15.8)
28 (18.1)
GSTM1 null cases (n, %)
38 (42.2) 91 (54.8) NA
NA NA 64 (55.2) 9 (69.2) 31 (57.4)
18 (36.7) 68 (53.1) 41 (47.7) 107 (35.4)
81 (51.6)
GSTM1 null controls (n, %) 105 (47.8)
54 (48.2)
NA
NA NA 23 (53.5) 72 (47.1)
20 (33.3)
102 (37.0)
122 (51) 48 (48.5)
140 (42.4)
92 (59.4)
Studies are listed by year of publication. Abbreviations: FAB, French-American-British classification; MDS, myelodysplastic syndrome; NA, not applicable; NR, not reported; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; WHO, World Health Organization classification.
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Figure 1. Forest plot for GSTT1 null polymorphism and MDS risk;
meta-analysis using a random effects model. Each study is shown
by the point estimate of the odds ratio (square proportional to the
weight of each study) and 95% confidence interval for the odds
ratio (extending lines); the summary odds ratio and 95%
confidence intervals by random effects calculations is depicted as
a diamond. For all figures, values higher than 1 indicate that the
null genotype is associated with increased risk of MDS
development. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
classification (FAB versus WHO), inclusion of secondary MDS cases (yes versus no), ethnicity of participants (Caucasian versus East Asian) and morphological diagnosis (RA/ RARS versus RAEB/RAEB-t).
Statistical analyses were performed using STATA (version 10/SE, Stata Corp., College Stage Station, Texas). Studies in the figures are listed by the year of publication.
Results
Eligible studies Out of 98 studies retrieved by our initial search strategy, 13 were considered eligible for this systematic review and were included in the meta-analysis; all studies investigated the GSTT1 and 10 also investigated the GSTM1 polymorphism (Table 1).7,2637
Studies had been conducted over a period of thirteen years (1996 to 2009). The vast majority of the studies (11 of 13) used the French-American-British (FAB) criteria to classify patients and only two used the more recent World Health Organization Criteria (WHO). Ten of the studies were conducted in Caucasian populations, two in East Asian populations, and one in a Latin American population. Hospital controls were used in seven studies and healthy controls (healthy volunteers, blood donors or newborns) were used in six studies. In general, studies were relatively small: mean number of cases was 113.15 (SD 80.4, range: 13323) and the mean number of controls was 146.7 (SD 89.57, range: 43330). Nine studies did not match cases to controls; controls were matched to cases for age and gender and in three
Figure 2. Forest plot for GSTM1 polymorphism and MDS risk;
meta-analysis using a random effects model. [Color figure can be
viewed in the online issue, which is available at
www.interscience.wiley.com.]
studies, for age, gender and smoking in one study. All studies used validated polymorphism detection methods, such as PCR or PCR-RFLP, with the majority employing multiplex PCR protocols to identify the GSTT1 and GSTM1 null genotypes along with control genes for reaction quality control.
The frequency of the GSTT1 null genotype among controls ranged from 30.2% to 46% in studies of East Asian populations and from 6.7% to 25% in studies of non-East Asian populations. The control group frequency of the GSTM1 null genotype was 53.5% in the one East Asian study that provided information and ranged from 33.3% to 59.4%% in studies of non-East Asian populations.
Evidence synthesis The studies investigating the GSTT1 polymorphism reported on a total of 1471 cases and 1907 controls. 376 cases (25.6%) had null genotypes compared to 340 (17.8%) controls. There was moderate between study heterogeneity (pQ 0.01) and inconsistency (I2 52.3%). Overall, the GSTT1 null genotype was associated with increased risk of MDS, fixed-effects OR 1.44 (95% CI, 1.211.72; p < 0.0001). Random effects models were also consistent with an association between the GSTT1 null genotype and MDS risk, OR 1.43 (95% CI, 1.091.89; p 0.01]. Figure 1 demonstrates the results of the metaanalysis of GSTT1 studies.
The studies investigating the GSTM1 polymorphism reported on a total of 1161 cases and 1668 controls. There was moderate between study heterogeneity (pQ 0.07) and inconsistency (I2 43.1%). Overall, the GSTM1 null genotype was not associated with increased risk of MDS, fixed effects OR 0.97 (95% CI, 0.831.14); p 0.69. Random effects models also did not demonstrate an association between GSTM1 genotypes and MDS risk, OR 1.02 (95% CI, 0.821.28); p 0.69. Figure 2 demonstrates the results of the meta-analysis of GSTM1 studies.
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Table 2. Results of meta-analysis and subgroup analysis. Significant results are highlighted in bold. All odds ratios (OR) are calculated using random effects models
Studies
GSTT1 Number of studies (cases/controls) OR ( 95% CI); p-value
Interaction p-value
GSTM1 Number of studies (cases/controls) OR (95% CI); p-value
Interaction p-value
All studies
13 studies, 1471/1907
NA
10 studies, 1161/1668
NA
1.43 (1.091.89)
1.02 (0.821.28)
p 0.01
p 0.85
No matching
9 studies, 852/1263
0.21
6 studies, 562/1024
0.77
1.57 (1.092.27)
1.08 (0.861.36)
p 0.02
p 0.52
Matched design
4 studies, 619/644
4 studies, 599/644
1.17 (0.881.56)
1.0 (0.631.57)
p 0.29
p 0.98
Healthy controls
6 studies, 831/1057
0.66
5 studies, 524/711
0.13
1.32 (1.031.71)
0.85 (0.661.11)
p 0.03
p 0.23
Hospital controls
7 studies, 640/850
5 studies, 637/957
1.49 (0.932.41)
1.17 (0.841.62)
p 0.10
p 0.35
FAB classification
11 studies, 1229/1653
0.36
8 studies, 918/1414
0.18
1.52 (1.122.07)
1.10 (0.841.46)
p 0.007
p 0.49
WHO classification
2 studies, 242/254
2 studies, 243/254
1.07 (0.542.10)
0.81 (0.571.16)
p 0.85
p 0.25
Exclusively de novo MDS
11 studies, 1169/1568
0.86
9 studies, 1033/1429
0.80
1.44 (1.032.03)
1.02 (0.791.33)
p 0.03
p 0.86
Includes secondary MDS
2 studies, 302/339
1 study, 128/239
1.37 (0.912.05)
1.09 (0.711.67)
p 0.13
p 0.79
Caucasian
10 studies, 1247/1538
0.83
8 studies, 996/1349
0.94
1.45 (1.061.99)
1.04 (0.791.37)
p 0.02
p 0.78
East Asian
2 studies, 175/93
1 study, 116/43
1.62 (0.624.26)
1.07 (0.532.16)
p 0.33
p 0.85
RA/RARS
6 studies, 360/825
NA
3 studies, 558/643
NA
1.68 (1.052.71)
0.89 (0.641.25)
p 0.03
p 0.51
RAEB/RAEB-t
7 studies, 342/978
4 studies, 571/796
1.31 (0.692.48)
0.98 (0.671.45)
p 0.42
p 0.93
Abbreviations: FAB, French-American-British; MDS, myelodysplastic syndrome; OR, odds ratio; RA/RARS, refractory anemia/refractory anemia with an excess of blasts; RAEB/RAEB-t, refractory anemia with an excess of blasts/refractory anemia with an excess of blasts in transformation; WHO, World Health Organization.
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Subgroup analysis
The results of subgroup analysis by ethnicity, control selection and morphological characteristics are presented in Table 2. The relatively small number of studies per subgroup and small number of participants did not allow for accurate estimation of ORs. The point estimates appeared consistent between subgroups and nominal significance was achieved for several subgroups regarding the GSTT1 polymorphisms. In general, ORs for the GSTT1 polymorphisms were consistent across subgroups and favored an increased risk of MDS for patients carrying the null genotype.
Potential for bias For the GSTT1 polymorphism there was no evidence of small study effects (Begg-Mazumdar's test p 0.67 and Egger's test p 0.79). For the GSTT1, the odds ratio of the first published study34 (OR 4.46, 95% CI 2.537.89) was statistically significantly different from the pooled odds ratio of all subsequent studies (random effects OR 1.27, 95% CI 1.061.54; interaction test p < 0.0001). Interestingly, removal of the first study also eliminated between-study heterogeneity (pQ 0.679; I2 0%). Over time the random effects OR for GSTT1 followed a decreasing trend (Figure 3). For the GSTM1 polymorphism there was there was some evidence of small study effects (Begg-Mazumdar's test p 0.03 and Egger's test p 0.02) but there was no evidence that the first study differed significantly from subsequent evidence.
Discussion This report is the first meta-analysis examining the effect of GSTT1 and GSTM1 polymorphisms on the risk of MDS. We found the null variant of GSTT1 to be associated with an increased MDS risk. Although less evidence is available, there was no indication for an association between GSTM1 and MDS. These polymorphisms have been investigated as potential risk factors for the development of many solid tumors, and convincing associations have been demonstrated for lung, prostate, colorectal, bladder, head and neck cancer as well as hepatocellular carcinoma.3843 A systematic review that investigated the association of GST null polymorphisms with acute leukemia, both myeloid and lymphoblastic found that GSTM1 and GSTT1, but not GSTP1 polymorphisms, appear to be associated with an increase in the risk of acute leukemia.44 Previous studies have established that the prevalence of the GSTT1 null genotype is lower among Caucasians (1020 percent) compared with Asians (5060 percent).45 MDS in Asian populations occurs at a younger age compared to Western populations, indicating a stronger genetic component.4648 We speculate that this difference may be partly ascribed to the higher prevalence of the GSTT1 null genotype among Asian populations.
The association of environmental toxin exposure and MDS development strongly supports the existence of gene environment interactions. MDS and acute leukemia form a pathogenetic and clinical continuum, with pro-apoptotic
Figure 3. Cumulative meta-analysis for GSTT1 polymorphism and
MDS risk using a random effects model. Each point estimate with
corresponding confidence intervals presents the meta-analysis
results as each study was published. Pooled odds ratios are
depicted as circles with extending lines representing 95% CI.
effects and cytopenias on one end and increased proliferation, blocked differentiation and high blast counts on the other. Given its significant association with both acute leukemia and MDS, the GSTT1 null genotype appears as a potential initiating risk factor for both conditions. Based on our analysis, the association of the GSTT1 null genotype with MDS is strengthened by the consistency of results across ethnic and morphological subtypes of disease.
Functional studies provide further support for the association between the GSTT1 null genotype and MDS. Benzene exposure has been associated with a variety of disorders, including MDS.49 The effects of benzene may be mediated by intermediate genotoxic and cytotoxic metabolites that induce DNA damage, including chromosomal aberrations and sister chromatid exchanges.50,51 Some benzene metabolites accumulate in the bone marrow where they undergo autoxidation, producing highly reactive oxygen species which are responsible for cell damage.52 Both GSTM1 and GSTT1 are involved in the detoxification of benzene oxide to s-phenylmercapturic acid.53 Several studies have examined the role of GSTM1 and GSTT1polymorphisms on biomarkers of benzene toxicity. Kim et al, reported an increased occurrence of chromosomal aberrations in subjects carrying the null genotype of both GSTM1 and GSTT1 relative to the heterozygotes or non-null individuals.51 In addition, the frequency of diepoxybutane-induced sister chromatid exchanges was significantly increased in GSTT1 null subjects.54
This study is limited by the unavailability of individual patient data that would allow the identification of geneenvironment interactions as well as the potential association of GST polymorphisms with specific disease characteristics such as cytogenetic abnormalities or somatic mutations. Be that as it may, by pooling the results of all
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published independent studies this review has increased power to detect the association between GST polymorphisms and MDS risk. Also, by including studies published over a long period of time, it has been possible to demonstrate that, apart from the somewhat exaggerated effect estimate of the first published study, the available evidence supports an association between the GSTT1 null genotype and MDS risk.
In conclusion, this review demonstrates that null polymorphisms in GSTT1, but not in GSTM1, are associated with increased odds of MDS development. Given the strong association between GSTT1 null genotype and MDS risk, as well as the established role of GSTs in environmental carcinogen detoxification and acute leukemia pathogenesis, studies to investigate potential gene-environment interactions are necessary across the myelodysplasia-leukemia spectrum.
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