Bipolar disorder and polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1)

Glutathione S-transferases are ubiquitous multifunctional enzymes, which play a key role in cellular detoxification. The present case-control study was performed in Shiraz, Iran to investigate the association between polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and susceptibility to bipolar disorder (BPD). A total of 228 BPD patients participated in the study. In addition, 236 healthy blood donors, who frequency matched with the patients according to age and gender, were also studied as a control group. Statistical analysis revealed that polymorphisms of neither GSTM1 (OR = 0.73, 95% CI: 0.50-1.05) nor GSTT1 (OR = 0.98, 95% CI: 0.65-1.47) were associated with risk of BPD. Patients were stratified according to their age of onset into early onset (below 19 years old) and late onset (more than 19 years old) groups. Among the early onset group, the GSTM1 null genotype decreases the risk of BPD (OR = 0.43, 95% CI: 0.24-0.79). Further analysis showed that a combination of “GSTM1 positive genotype and GSTT1 null genotype” versus “positive genotypes of GSTM1 and GSTT1” increased the risk of BPD (OR = 2.28, 95% CI: 1.07-4.85). However, there was no significant association between the study polymorphisms and risk of BPD among the late onset group. The present finding indicated that GSTM1 and GSTT1 are candidate polymorphisms for susceptibility to BDP among adolescents.     

Association analysis of GSTT1, GSTM1 genotype polymorphisms and serum total GST activity with ischemic stroke risk

Oxidative stress plays a major role in pathogenesis of atherosclerosis which is responsible for stroke. Glutathione S-transferases (GSTs) detoxify metabolites produced by oxidative stress within the cell and protect the cells against injury. This study aimed to investigate the association of polymorphisms in GSTT1, GSTM1 genes and GST activity with ischemic stroke risk. Patients had almost the same GST activity as that of controls. No significant differences were found between patients and controls in terms of GSTT1 null, GSTM1 null and GSTT1/GSTM1 double null genotype frequencies. Besides, both patients and controls with double GSTT1/GSTM1 null genotypes had the lowest serum GST activities. Compared to the present genotypes, GSTT1 null (OR = 4.888; P = 0.006) and GSTM1 null (OR = 2.383; P = 0.011) genotype groups contained relatively more hypertensive stroke patients. This study showed that GSTT1 and GSTM1 null genotypes, together with hypertension, may play a significant role in the pathogenesis of ischemic stroke.     

Interaction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders

We investigated the role of glutathione S-transferase (GST) genes in Autism Spectrum Disorder (ASD). We used data from 111 pairs of age- and sex-matched ASD cases and typically developing (TD) controls between 2 and 8 years of age from Jamaica to investigate the role of GST pi 1 (GSTP1), GST theta 1 (GSTT1), and GST mu 1 (GSTM1) polymorphisms in susceptibility to ASD. In univariable conditional logistic regression models we did not observe significant associations between ASD status and GSTT1, GSTM1, or GSTP1 genotype (all P > 0.15). However, in multivariable conditional logistic regression models, we identified a significant interaction between GSTP1 and GSTT1 in relation to ASD. Specifically, in children heterozygous for the GSTP1 Ile105Val polymorphism, the odds of ASD was significantly higher in those with the null GSTT1 genotype than those with the other genotypes [matched odds ratio (MOR) = 2.97, 95% CI (1.09, 8.01), P = 0.03]. Replication in other populations is warranted.     

Glutathione-S-transferase T1 and M1 gene polymorphisms in Greek patients with multiple sclerosis: a pilot study

Oxidative stress has been implicated in the pathogenesis of multiple sclerosis (MS). Glutathione- S -transferases (GSTs) are detoxification enzymes, evolved to protect cells against reactive oxygen metabolites. Both GSTT1 and GSTM1 genes exhibit a homozygous deletion polymorphism (null genotype) leading to abolished enzyme activity. We studied the impact of the GSTT1 and GSTM1 polymorphisms on MS susceptibility in a case–control study of 47 Greek patients and 165 controls. Correlations between genotype, gender and disability status were also investigated. The incidence of both GSTT1 and GSTM1 genotypes did not differ significantly between controls and patients. A significantly increased frequency of GSTM1 null genotype was found amongst female patients (65.5%) as compared with males (33.3%, P  =0.04). The results suggest that GSTT1 and GSTM1 have no major pathogenetic role on the MS occurrence, nor any strong modifying effect on the disability status. The higher incidence of GSTM1 null genotype observed in female patients, suggests a possible role of the GSTM1 detoxification pathway in a gender-dependent manner.     

Association of glutathione S-transferase T1 and M1 gene polymorphisms with ischemic stroke risk in the Chinese Han population

Atherosclerosis plays an important role in ischemic stroke, and oxidative stress participates in the entire process of atherosclerosis. Glutathione S-transferase (GST) acting with other antioxidant enzymes can eliminate reactive oxygen species and protect cells against oxidative damage. To assess the association of glutathione S-transferase (GSTT1 and GSTM1) gene polymorphisms with ischemic stroke in the Chinese Han population, the present study selected 315 patients with ischemic stroke and 210 healthy controls for comparison. GSTT1 and GSTM1 genotypes were determined using polymerase chain reactions, electrophoresis and imaging analysis. No obvious evidence of GSTT1-null, GSTM1-null and GSTT1/GSTM1-double null genotype distribution differences was found between case and control groups or between genders. Subgroup analysis showed that the risk of stroke was increased when hypertension was accompanied by GSTT1-null (odds ratio (OR) = 2.996, P < 0.001) and GSTM1-null (OR = 3.680, P < 0.001) genotypes; diabetes mellitus was accompanied by GSTT1-null (OR = 1.860, P = 0.031) and GSTM1-null (OR = 2.444, P = 0.002) genotypes, and smokers showed a GSTT1-null genotype (OR = 2.276, P = 0.003). GSTT1- and GSTM1-null genotypes may interact synergistically with hypertension, diabetes mellitus and smoking to increase the incidence risk of ischemic stroke.     

Glutathione S-transferase polymorphism in Parkinson's disease

Summary. Glutathione S-transferases (GSTs) are involved in the detoxification of endogenous or exogenous toxins, which may play a role in the pathogenesis of Parkinson's disease. We genotyped the Glutathione-S-Transferase isoenzymes GSTM1 and GSTT1 by polymerase chain reaction in order to evaluate different gene polymorphisms of these isoenzymes in 149 parkinsonian and 99 control subjects. No differences appeared between both groups regarding the frequencies of the homozygous deletion of GSTM1 (odds ratio 1.021; 95% Cl [0.613; 1.699], p < 0.521 Fisher's exact test) and GSTT1 (odds ratio 1.514; 95% Cl [0.811; 2.824], p < 0.127). Age of onset of PD did notcorrelate to GSTM1 and GSTT1 polymorphisms. These results do not support the hypothesis of a possible impact of GSTM1 and GSTT1 detoxification activities in the pathogenesis of Parkinson's disease. Received March 26, 1999; accepted August 18, 1999     

MEIS1, a Promising Candidate Gene,Is Not Associated with the Core Symptoms of Antipsychotic-Induced Restless Legs Syndrome in Korean Schizophrenia Patients

ObjectiveRestless legs syndrome (RLS) is a distressing sleep disorder to which individuals appear to be genetically predisposed. In the present study, we assumed that antipsychotic-induced RLS symptoms were attributable to differences in individual genetic susceptibility, and investigated whether MEIS1, a promising candidate gene, was associated with antipsychotic-induced RLS symptoms in schizophrenia patients.MethodsAll subjects were diagnosed with schizophrenia by board-certified psychiatrists using the Korean version of the Structured Clinical Interview for DSM-IV. We assessed antipsychotic-induced RLS symptoms in 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group. Genotyping was performed for the rs2300478 and rs6710341 polymorphisms of the MEIS1 gene.ResultsWe divided subjects into RLS symptom (n=96) and non-symptom (n=94) groups. There was no significant between-group difference in the genotype or allele frequencies of the two polymorphisms investigated, nor in the frequency of the rs2300478-rs6710341 haplotype.ConclusionOur data do not suggest that the rs2300478 and rs6710341 polymorphisms of the MEIS1 gene are associated with the core symptoms of antipsychotic-induced RLS in schizophrenia; different genetic mechanisms may underlie antipsychotic-induced vs. primary RLS.     

Effects of glutathione S-transferase M1 and T1 deletions on Parkinson's disease risk among a North African population

PurposeIn this study, the effects of glutathione S-transferase polymorphisms Mu1 (GSTM1) and glutathione S-transferase polymorphisms Theta1 (GSTT1) on Parkinson's disease (PD) risk factor were evaluated in a Tunisian population.MethodsThese polymorphisms were analyzed in 229 healthy Tunisian subjects and 64 Tunisian patients with PD, using a polymerase chain reaction (PCR). Statistical analysis was performed using SPSS 18.0. The relative associations between the GST genotypes and PD were assessed by calculating the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe study results demonstrated that the individuals with GSTM1 [OR = 3.93, 95% CI: 1.98–7.92, P = 10^?6] and GSTT1 [OR = 5.45, 95% CI: 2.90–10.30, p = 10^?6] were statistically associated with the risk of PD. A significant association was also found between the individuals with both GSTM1/T1 null genotypes and PD risk [OR = 22.10, 95% CI: 6.99–73.75, P = 10^?6].ConclusionThese genotyping findings suggest that the absence of both GSTM1 and GSTT1 activity could be a contributory factor for the development of PD.     

Sexual dimorphism in xenobiotic genetic variants-mediated risk for Parkinson’s disease

The vulnerability of dopaminergic neurons to environmental exposures in sporadic Parkinson’s disease (PD) has been attributed to altered detoxification by xenobiotic metabolizing genes. Hence, we investigated the influence of genetic polymorphisms in xenobiotic metabolic pathway (CYP1A1 m1, CYP1A1 m2, CYP1A1 m4, COMT p.H108L, GSTT1, and GSTM1) on the susceptibility to PD. We used PCR–RFLP for CYP1A1 and COMT genotyping; multiplex-PCR for GSTT1 and GSTM1 deletion analysis; and spectrophotometric methods to evaluate the oxidative stress markers. Results showed association of CYP1A1 m1 (OR: 2.38, 95 % CI: 1.76–3.22) and COMT p.H108L (OR: 2.08 95 % CI: 1.56–2.77) polymorphisms with risk for PD. Male patients carrying combination of COMT p.H108L and CYP1A1 m1 variant alleles showed an early onset of the disease. There was a significant increase in oxidative stress makers such as malondialdehyde and protein carbonyls; and decrease in glutathione levels in PD cases compared to controls (P < 0.05). To conclude, CYP1A1 m1, COMT p.H108L polymorphisms were associated with PD risk, and sexual dimorphism was observed in these associations.     

Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A,DRD3 and SNAP-25 Genes

The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25 KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine β-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results.     

河北省健康人群谷胱甘肽硫转移酶T1、M1基因多态性的研究

目的探讨河北省健康人群谷胱甘肽硫转移酶T1、M1基因多态性的分布情况。方法应用内对照聚合酶链式反应技术(PCR)和凝胶成像分析方法对210例河北石家庄地区健康个体GSTT1、GSTM1基因进行检测分析。结果河北健康人群GSTT1、GSTM1基因缺失型的检出频率分别为48.6%和59.0%。同时具有GSTT1基因缺失型和GSTM1基因缺失型个体的检出频率为31.9%。结论GSTT1、GSTM1基因多态性在不同年龄、性别、生活习惯人群中分布差异无显著性。GSTT1、GSTM1基因在人群中的分布相互独立,无明显关联。GSTT1、GSTM1基因多态性的分布在不同地区,不同人种之间存在一定的差异。     

GST polymorphisms,interaction with smoking and pesticide use,and risk for Parkinson’s disease in a Japanese population

Patients with idiopathic Parkinson’s disease (PD) appear to have reduced capacity for detoxification of certain environmental compounds. The glutathione S-transferases (GSTs) are candidate genes for PD because they are involved in the metabolism of pesticides and cigarette smoke. We investigated the relationship of the seven GST polymorphisms (GSTM1 deletion, GSTT1 deletion, GSTP1 rs1695, GSTO1 rs4925, GSTO1 rs11191972, GSTO2 rs156697 and GSTO2 rs2297235) and PD risk with special reference to the interaction with pesticide use or cigarette smoking among 238 patients with PD cases and 370 controls in a Japanese population. None of the GST polymorphisms were associated with PD. GSTO1 rs4925 and GSTO2 rs2297235 were found to be in strong linkage disequilibrium (D′ = 0.98). Cigarette smoking was significantly associated with decreased risk of PD. However, no interaction of smoking with any of the GST polymorphisms was observed. Self-reported pesticide use was not associated with increased risk of PD. There was no evidence of interaction between self-reported pesticide use and either GST polymorphism. Our results suggest that the tested GST polymorphisms did not play an important role in PD susceptibility in our Japanese population. Our study does not give evidence of interaction between the GST polymorphisms and smoking may although this study provided sufficient statistical power to detect modest interaction. As for interaction between GSTP polymorphisms and pesticide use, the power of this study to detect an interactive effect was low due to a small number of pesticide users. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the GST polymorphisms in PD development.     

Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction

Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited.     

A case‐control study of Parkinson's disease and tobacco use: Gene‐tobacco interactions

A case‐control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age‐matched and gender‐matched controls. Participants completed an interviewer‐administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene‐tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1‐1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation. © 2010 Movement Disorder Society     

Glutathione s-transferase gene polymorphism and ischemic cerebrovascular disease

Glutathione S-transferase polymorphisms (GST) were examined in 142 cases with ischemic cerebrovascular disease (ICVD) to explore whether the GST polymorphisms confer a risk to an individual to develop ICVD. Tobacco smoke is a major cause of both cancer and vascular disease. The subjects were therefore stratified with ICVD for smoking status, and then the authors examined whether polymorphisms in this detoxification enzyme gene, GST, influence risk of ICVD. The GST genotype was analyzed by the polymerase chain reaction. Neither GSTM1 nor GSTT1 genotypes in the ICVD group was significantly different from the control group (n=344), even in smokers. The authors attempted the combined analysis for GSTM1 and GSTT1 genotypes in ICVD for smoking status. No significant association was observed among the combined genotypes and ICVD. The observations do not confirm the effect of the GSTM1 and GSTT1 genotypes as a risk factor for ICVD, even in smokers. However, this approach provides a way of addressing the hypothesis that environmental genotoxins could play a role in the etiopathogenesis of ICVD.     

Genetic Susceptibility in Solvent Induced Neurobehavioral Effects

The aim of this investigation was to study the influence of genetic polymorphisms of biotransformation enzymes and dopamine receptors on neurobehavioral effects in referents (n = 53), solvent-workers (n = 144), and chronic toxic encephalopathy (CTE) patients (n = 33). All participants were interviewed for exposure data and confounding factors and underwent a clinical examination. Neurobehavioral complaints (neurotoxicity symptom checklist-60) and effects [simple reaction time (SRT), symbol digit substitution (SDS), hand–eye coordination (HEC), and digit span backwards (DSB)] were evaluated with a computer assisted test battery. The following genotypes were determined: GSTM1, GSTT1, GSTP1, DRD2 Taq1A, DRD2 Taq1B, and DRD2-141Cdel. Neurotoxic effects and complaints were significantly higher in CTE patients and were related to both duration and level of exposure. An equal distribution of genotypes was found between all groups. Logistic regression analysis revealed that GSTT1 was negatively associated with sleep and sensorimotor complaints. GSTM1 had a protecting influence on the relationship between logDSB and the cumulative exposure index and between logSRT and cumulative exposure index and degree of exposure, respectively. This effect was also found when correcting for age, education level, alcohol consumption, and smoking. DRD2-141Cdel polymorphisms had a negative influence on the relationship between logSDS and the total exposure time. GSTT1 might be protective against sleep and sensorimotor complaints, whereas GSTM1 seems to decrease sustained attention and short-term memory problems in relation to solvent exposure. Individuals possessing DRD2-141Cdel variant experienced more visuomotor problems.     

No association between EGR gene family polymorphisms and schizophrenia in the Chinese population

Early growth response (EGR) genes are thought to have a role in the pathogenesis of schizophrenia because of their conserved DNA binding domain and biologically activity in neuronal plasticity. This zinc-finger motif could influence gene post-translational modification and expression. The multigenetic association model, using markers in genes of similar or antagonistic biological effects within a signal pathway or gene family, might be more appropriate to this aspect of the schizophrenia hypothesis than the single gene strategy. In this study we investigated the role of EGR1, EGR2, EGR3 and EGR4 within the EGR family. Taqman technology was used to examine 12 single nucleotide polymorphisms (SNPs) covering these four genes in 2044 Chinese Han subjects. Case–control analyses were performed to detect association of these 4 genes with schizophrenia and multifactor dimensionality reduction (MDR) analysis was employed to examine their potential gene–gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1–4 and the risk of schizophrenia nor was any such association found with regard to interaction within EGR1–4 (p_min = 0.623, CV Consistency = 10/10). We concluded that although multiple candidate genes are involved in schizophrenogenic development, the EGR family may not play a major role in schizophrenia susceptibility in the Chinese Han population.     

Genetic Variation in Glutathione S-Transferase Genes and Risk of Nonfatal Cerebral Stroke in Patients Suffering from Essential Hypertension

Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants has been implicated in pathogenesis of cerebral stroke. The purpose of this study was to investigate the relationship between common polymorphisms of glutathione S-transferase M1, T1, and P1 genes and risk of stroke in hypertensive individuals. A total of 667 unrelated Russian individuals with hypertension, including 306 hypertensives who suffered from cerebral stroke and 361 hypertensives who did not have cerebrovascular accidents, were recruited for the study. The deletion polymorphisms of GSTM1 and GSTT1 genes and polymorphism Ile105Val of the GSTP1 gene were genotyped by a multiplex polymerase chain reaction and restriction analyses, respectively. No differences in GSTM1 and GSTP1 genotype distributions between the cases and controls have been observed. The null GSTT1 genotype was found to be associated with increased risk of cerebral stroke after Bonferroni correction and adjusting for confounding variables such as gender, blood pressure, body mass index, and antihypertensive medication use (odds ratio 1.51 95?% CI 1.09-2.07, P?=?0.01). The present study was the first to show the association of null genotype of the GSTT1 gene with increased risk of cerebral stroke.     

Genetic variant of glutathione peroxidase 1 in autism

Genetic factors can contribute to autistic disorder (AD). Abnormal genes of oxidative stress pathways and increased oxidative stress have been reported in autism spectrum disorders. Polymorphisms of genes involved in glutathione metabolism, e.g. GSTP1 and GSTM1 are reportedly associated with autistic disorder. We investigated a GCG repeat polymorphism of a human glutathione peroxidase (GPX1) polyalanine repeat (ALA5, ALA6 and ALA7) in 103 trios of AD (probands and parents) using the transmission disequilibrium test. Significant transmission disequilibrium (p = 0.044) was found in the overall transmission of the three alleles. The ALA6 allele was under transmitted (p = 0.017). These results suggest that possessing this ALA6 allele may be protective for AD. Future study of interaction of the GPX1 GCG repeat and other gene polymorphisms such as the MnSOD ALA16 or the GPX1 Pro198Leu polymorphism in this cohort of AD families may shed light in whether the combination of the ALA6 allele with another polymorphism of antioxidant allele contributes to the increased oxidative stress in autism.