Molecular Human Reproduction, Vol. 9, No. 3, 165-169,
March 2003
© 2003 European Society of Human Reproduction and Embryology
Article |
Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss
Submitted on May 31, 2002; resubmitted on August 29, 2002. accepted on December 13, 2002
1 Department of Public Heath, Hokkaido University Graduate School of Medicine and 2 Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
3 To whom correspondence should be addressed. e-mail: fsata{at}med.hokudai.ac.jp
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ABSTRACT |
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The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. A case–control study of 115 cases with RPL and 160 controls was conducted. All cases and controls were women resident in Sapporo, Japan and the surrounding area. They were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1 null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36–3.66]. On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1 null genotype (OR = 0.95; 95% CI = 0.58–1.55). The results suggest that women with GSTM1 null polymorphism may therefore have an increased risk of RPL.
Key words: genetic polymorphism/glutathione S-transferase M1/glutathione S-transferase T1/molecular epidemiology/recurrent pregnancy loss
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Introduction |
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About 10–14% of clinically recognized pregnancies end in pregnancy loss in the Japanese population as in Caucasians. The aetiology of recurrent pregnancy loss (RPL) remains largely unclear (Stirrat, 1990; Parazzini et al., 1991; Cramer and Wise, 2000). Epidemiological studies have suggested that the condition might be multifactorial with a possible genetic predisposition and involvement of environmental factors in its pathogenesis (Fenster et al., 1991; Parazzini et al., 1991; Cramer and Wise, 2000).
Enzymes belonging to the glutathione S-transferase (GST) and cytochrome P450 (CYP) families are involved in the two-stage detoxification process of a wide range of environmental toxins and carcinogens. The genes for these enzymes are part of the aryl hydrocarbon (Ah) gene family and are under Ah receptor control (Nebert and Gonzalez, 1987). The Ah receptor binds a number of different classes of chemicals, including halogenated aromatics such as dioxin and polycyclic aromatic hydrocarbons, which induce transcription of the genes in this family (Safe, 1995).
The GST are a family of enzymes that are believed to exert a critical role in cellular protection against toxic foreign chemicals and oxidative stress (Hayes and Strange, 2000). These enzymes not only catalyse the conjugation of glutathione (GSH) to a variety of electrophilic compounds (Strange et al., 2000), but also detoxify organic peroxides, acting as non-selenium-dependent GSH peroxidases (Ketterer and Meyer, 1989). Seven GST gene families encoding cytosolic enzymes have been described. The GSTM1 gene belongs to the mu GST family, and the GSTT1 gene belongs to the theta family. Phenotypic absence of enzyme activity is due to inheritance of a homozygous deletion of the whole gene, i.e. the ‘null’ genotype. Generally, the GSTM1 null and GSTT1 null genotypes are considered to be an indicator of a high risk of disease (Strange et al., 2000). GSTM1 is important in detoxification of carcinogens in tobacco smoke, including polycyclic aromatic hydrocarbons (Harris, 1991; Nebert, 1991). Initially, many studies on GST polymorphism and susceptibility concentrated on tobacco-related cancer (Rebbeck, 1997; Strange and Fryer, 1999). Many data on GSTM1 are inconsistent and its influence on risk remains unclear. There is less information on the influence of GSTT1 and no associations have been reported (Strange et al., 2000).
A large number of structurally diverse xenobiotics are known to be substrates for the GST. Some substrates have relatively high specific activity with one or a few isoenzymes within a class and little or no activity within other classes (Whalen and Boyer, 1998). Allelic variants of GST that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to reproductive toxicity, which could lead to endometriosis, RPL or poor pregnancy outcome (Hirvonen et al., 1996; Baranov et al., 1996; Baranova et al., 1997, 1999; Strange and Fryer, 1999; Zusterzeel et al., 2000; Arvanitis et al., 2001; Hadfield et al., 2001; Wang et al., 2002). The genes encoding the enzymes GSTM1 and GSTT1 have been studied largely because of data suggesting that exposure to environmental pollutants, in particular dioxins, may be implicated in the aetiology of these diseases (Rier et al., 1993). RPL is believed to be associated with various environmental toxins and teratogens such as organic solvents, alcohol, heavy metals and ionizing radiation, but scientifically accurate information regarding the reproductive impact of potential environmental toxins and other teratogens is not readily available (Gardella and Hill, 2000). The aim of this study was to investigate the role of GSTM1 and GSTT1 polymorphisms (which lead to impaired detoxification functions in the corresponding protein) in the pathogenesis of RPL.
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Materials and methods |
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This case–control study was performed in the city of Sapporo, Japan, during the years 1999–2002. We studied 115 patients aged 20–43 years with a history of RPL and 160 controls aged 21–54 years who were referred to Hokkaido University Hospital. The characteristics of the study groups are shown in Table I. RPL was defined as having a history of two or more spontaneous consecutive miscarriages and stillbirths. The primary RPL group comprised 101 women with a history of two or more pregnancy losses but no live birth. The 14 secondary RPL women experienced two or more pregnancy losses after at least one live birth. A total of 106 miscarriages happened in the first trimester. All women with RPL were subjected to examination by ultrasound and hysterosalpingography for detection of anatomical abnormalities of the genital tract and to chromosome karyotypic analyses of peripheral blood. Women with RPL who had balanced type chromosomal translocation or a uterine conformational abnormality such as septate uterus were excluded from this study. The control women consisted of 160 volunteers experiencing at least one live birth and no abortion who had no history of endometriosis or infertility. There were no significant differences in age between cases and controls. This study was conducted with all the subjects’ informed consent and approved by the institutional ethical board for human gene and genome studies of Hokkaido University Graduate School of Medicine.
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Genomic DNA was extracted from lymphocytes of peripheral blood samples by standard techniques. The multiplex PCR method was used to detect the presence or absence of the GSTM1 and GSTT1 genes as described by Chen et al. (1996) with slight modifications. Briefly, an aliquot of 100 ng of DNA was mixed with 0.6 µmol/l each of GST primers (GSTM1 forward, 5'-GAACTCCCTGAAAAGCTAAAG C-3' and reverse, 5'-GTTGGGCTC AAATATACGGTGG-3'; GSTT1 forward, 5'-TTCCTTACTGGTCCTC ACATCTC-3' and reverse, 5'-TCACCGGATCATGGCCAGCA-3'), and 0.2 µmol/l each of ß-globin primers (forward, 5'-CAACTTCATCCAC GTTCACC-3' and reverse, 5'-GAAGAGCCAAGGACAGGTAC-3'), 1.25 IU of Taq polymerase (AmpliTaq Gold; Applied Biosystems Japan, Tokyo, Japan) with 3.3 mmol/l MgCl2 and 200 µmol/l dNTP in a total volume of 50 µl of PCR buffer provided by the manufacturer. The PCR procedure was as follows: an initial denaturation step at 94°C for 10 min, and then amplification for 35 cycles at 94°C for 15 s, 60°C for 30 s and 72°C for 1 min, followed by a final extension step at 72°C for 7 min. The PCR products were separated by 3% agarose gel electrophoresis and identified with ethidium bromide staining.
We calculated the age-adjusted odds ratios (OR) and 95% confidence intervals (CI) associated with the GST genotypes by unconditional logistic regression analysis. All analyses were conducted using SPSS software for Windows (SPSS Inc., Chicago, IL, USA).
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Results |
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The frequencies of the GSTM1 and GSTT1 genotypes were compared between 115 patients with RPL and 160 controls in a Japanese population (Table II). The GSTM1 null genotype was more frequently found in women with RPL than in the controls (OR = 2.23, 95% CI = 1.36–3.66). There was no significant evidence that the distribution of the GSTT1 genotype differed between the patients and the controls, with an OR = 0.95 (95% CI = 0.58–1.55). We also investigated whether the risk of pregnancy loss was affected by GST genotype combinations. The reference group consisted of individuals with a putative low-risk genotype combination, i.e. GSTM1 present and GSTT1 present. There was a tendency for an increased risk of pregnancy loss with an increasing number of putative high-risk genotypes, except in the group expressing both null genotypes. The increase in risk seemed to be associated with the GSTM1 null genotype, which was in accordance with our findings for each GST gene.
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We evaluated the risk of pregnancy loss in the subgroups of patients according to the type of RPL (primary or secondary), the number of pregnancy losses, and age of gestation when pregnancy loss occurred. We found a positive association between risk of pregnancy loss and the GSTM1 null genotype in all the subgroups (Table III). In both the primary and the secondary RPL groups the frequency of the GSTM1 null genotype was high compared with the control group. Among women with primary RPL, the OR was 2.15 (95% CI = 1.29–3.60), and among women with secondary RPL, the OR was 3.02 (95% CI = 0.90–10.1); this was not significant, however, probably due to the small number of women in the secondary RPL group. Among women with three or more pregnancy losses, the GSTM1 null genotype showed a significantly increased risk of pregnancy loss (OR = 2.90, 95% CI = 1.58–5.34). A similar tendency was observed among women with only two pregnancy losses, but again it was not significant. The 63 women whose pregnancy losses occurred at <9 weeks of gestation accounted for >50% of all the cases and were designated the early RPL group. The remaining 52 women (45.2%) suffered one or more pregnancy losses at
9 weeks of gestation, and were designated the non-early RPL group. Both the early and non-early RPL groups showed high frequencies of the GSTM1 null genotype. Among women in the early RPL group, the OR was 2.39 (95% CI = 1.30–4.40). In the non-early RPL group it was 2.07 (95% CI = 1.09–3.95). There was no significant evidence that the GSTT1 genotype affected the risk of pregnancy loss in any subgroup.
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Discussion |
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In the present study, we demonstrated an association between RPL and the GSTM1 null genotype in a Japanese population. This association was observed in all subgroups of cases with RPL. It has previously been reported that the human GSTM1 null genotype is associated with a high inducibility of CYP1A1 gene transcription by dioxin. The presence of at least one GSTM1 allele was correlated with induction of only low levels of CYP1A1 mRNA (Vaury et al., 1995). Polymorphic variants in the phase I enzyme CYP genes may lead to increased toxification, whereas polymorphisms in the phase II enzyme GST genes may result in impaired detoxification (Zusterzeel et al., 2000). The risk of pregnancy loss associated with exposure to endogenous or exogenous substances may be modified by the genetic variations in individual metabolic detoxification activities; thus, in the phase I/phase II balance (Hirvonen et al., 1996; Wang et al., 1998).
The role of the GSTM1 null genotype in association with RPL has been studied but the results remain controversial (Hirvonen et al., 1996; Mendola et al., 1998; Zusterzeel et al., 2000). Hirvonen et al. (1996) reported an association between RPL and the GSTM1 null genotype in North Carolina, whereas there was an inverse association between risk of spontaneous abortion and the null genotype in New York. These studies were composed of only 29 cases in North Carolina and 89 cases in New York respectively. Mendola et al. (1998) and Zusterzeel et al. (2000) failed to detect any association between RPL and the GSTM1 genotype, although several environmental factors such as smoking cigarettes and consumption of alcohol or caffeine were taken into account (Mendola et al., 1998; Zusterzeel et al., 2000). Mendola et al. studied 32 cases in western New York and Zusterzeel et al. studied 187 cases in The Netherlands. Additionally, the latter study found an association between GSTP1 polymorphism and RPL (Zusterzeel et al., 2000). To the best of our knowledge, we have, for the first time, demonstrated an association between the risk of RPL and the GSTM1 null genotype by assessing a relatively large number of subjects.
According to the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database, a lower frequency of the GSTM1 null genotype was observed in the Japanese population (Garte et al., 2001). A Japanese control populaton showed a 47.5% frequency of the GSTM1 null genotype, whereas Caucasian control populations showed higher frequencies, 54.3% in USA and 50.4% in The Netherlands. The low frequency of the GSTM1 null genotype in the Japanese control population may be one of many factors that allowed for a statistically significant risk of RPL in the present study to be observed. On the other hand, an association between endometriosis and the GSTM1 null genotype has been reported in Caucasian populations (Baranov et al., 1996; Baranova et al., 1997, 1999). The role of the GSTT1 enzyme alone in reproductive organs is unclear although it has been reported that the combination of GSTM1 null and GSTT1 null is associated with a reduced survival rate in women with epithelial ovarian cancer (Howells et al., 1998). In the present study, we did not detect any association between the GSTT1 genotype and RPL. This is consistent with previous findings (Zusterzeel et al., 2000). The metabolic polymorphisms related to RPL or endometriosis in Asian populations have not yet been investigated.
Although pregnancy loss is a common occurrence, its environmental determinants are largely unknown. Heavy metals such as lead and mercury, organic solvents, alcohol and ionized radiation are confirmed environmental teratogens, and exposure could contribute to pregnancy loss (Gardella and Hill, 2000). Caffeine, cigarette smoking and hyperthermia are suspected teratogens, and the teratogenic impact of pesticides remains unknown (Gardella and Hill, 2000). More than 35 000 pesticides are registered with the US Environmental Protection Agency, and 3600 food addictives are approved by the US Food and Drug Administration for routine use (Dwivedi and Iannaccone, 1998). The number of chemicals in use was estimated to be >80 000 by the end of the last century (Dwivedi and Iannaccone, 1998). In Japan as well as in the USA, a large number of chemicals has been produced and used, and this has resulted in serious environmental pollution. However, most studies of reproductive effects in humans have been limited to date by their small size and insufficient exposure assessment. Therefore, scientifically accurate information regarding the reproductive impact of potential environmental toxins and other teratogens is not readily available (Gardella and Hill, 2000).
Metabolic pathways of xenobiotics include their activation during phase I of the biotransformation process followed by conjugation of highly toxic intermediate metabolic products during phase II (Baranova et al., 1999). Therefore, expression of phase I and II enzymes must be well coordinated. The genes which code for foreign-compound-metabolizing enzymes are highly polymorphic, so the presence of deletions can provoke imbalanced interactions of phase I and II. In relation to environmentally induced diseases, the supergene families of CYP and GST play key roles. The fact that high frequencies of the GSTM1 null genotype have been found in patients with lung cancer, bladder cancer, cutaneous tumours, chronic bronchitis, and endometriosis, which are regarded as environmentally induced, demands special attention (Baranova et al., 1997). A large number of structurally diverse xenobiotics are known to be substrates for the GST. Some substrates have relatively high specific activities with one or a few isoenzymes within one class and little or no activity within other classes (Whalen and Boyer, 1998). Further investigations of GST and xenobiotic pathways in patients with RPL are thus needed.
In the present study, a positive association between the risk of pregnancy loss and the GSTM1 null genotype in subgroups of RPL was found. We found a relatively higher RPL risk of GSTM1 null among women with three or more pregnancy losses (OR = 2.90) and among women who experienced only early pregnancy losses (OR = 2.39). Women with three or more pregnancy losses have more severe RPL. They have poorer reproductive outcomes in subsequent pregnancies than do women with two pregnancy losses. The GSTM1 null genotype might be closely related to severe RPL and early pregnancy loss. According to the frequencies observed in this study, 106 cases and 106 controls would detect an OR of 2.3 with 80% power (
= 0.05), and 68 cases and 68 controls would detect an OR of 2.9 with the same power (Browner et al., 2001). The association studies of all the cases with RPL and of the cases with three or more pregnancy losses had >80% power, and the study of the primary RPL subgroup had almost 80% power. The other studies, however, presented in the small subgroups, especially in the secondary RPL subgroup and in the cases with two pregnancy losses, lacked the power to find any association.
The observed association between RPL and the GSTM1 null genotype in the small subgroups may justify further investigations in a larger study, taking into account environmental factors such as caffeine intake, smoking and occupational or regional exposure to chemicals. Indeed, it was recently found that the risk of reduced birthweight in pregnant women carring CYP1A1 Aa/aa and GSTT1 null genotypes was enhanced by maternal cigarette smoking, suggesting an interaction between metabolic genes and cigarette smoking (Wang et al., 2002).
In conclusion, it is suggested that women with GSTM1 null polymorphism may have an increased risk of RPL, especially frequent or early RPL.
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Acknowledgements |
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This work was supported in part by Grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science and the Japan Ministry of Health, Labour and Welfare.
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