Association between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder

doi:10.1016/j.psychres.2011.09.002

Psychiatry Research

Volume 198, Issue 1, 30 June 2012, Pages 166-168

https://doi.org/10.1016/j.psychres.2011.09.002 Get rights and content

Abstract

The association between polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder (BPD) is investigated. This study was performed on 228 BPD patients and 234 control subjects. Among early-onset patients, the variant alleles of Glu32Lys and G-1002A increased BPD susceptibility. The haplotype “-1002 G, 32Glu, 42Gly” versus the other haplotypes was significantly decreased among early-onset patients compared to controls (P = 0.016).

Introduction

Studies indicate that bipolar disorder (BPD) is a multifactorial disorder affected by genetic and environmental factors (Craddock and Jones, 1999, Shih et al., 2004). The exact genes involved in its pathogenesis have yet to be discovered. A meta-analytic study suggests that oxidative stress may play an important role in the pathogenesis of BPD (Andreazza et al., 2008).

Glutathione S-transferases (GSTs) are the enzymes involved in the biotransformation of xenobiotic/endobiotics, and they can decrease the oxidative stress. Glutathione S-transferase Z1 (GSTZ1; MIM: 603758) is an enzyme with both transferase and isomerase activity. Although it exhibited limited activity with known GST substrates, it mainly catalyzes the biotransformation of malylacetoacetate to fumarylacetoacetate, the penultimate step in the Phenylalanine/Tyrosine degradation pathway (Board et al., 1997, Fernandez-Canon and Penalva, 1998). GSTZ1 is expressed in brain (Lantum et al., 2002).

A number of genetic polymorphisms have been detected in the coding and promoter region of the GSTZ1 gene. These polymorphisms have significant impact on the protein's kinetic characteristics and/or its expression level (Blackburn et al., 2000, Fang et al., 2006).

The association between genetic polymorphisms of several members of GST family (GSTM1, GSTT1, GSTZ1 and GSTP1) and the risk of schizophrenia was investigated (Harada et al., 2001, Pae et al., 2003, Saadat et al., 2007, Nafissi et al., 2011). It has been suggested that BPD and schizophrenia share some susceptibility genes due to the overlap in regions found to be linked to each disorder (Kelsoe, 1999, Berrettini, 2000, Park et al., 2004). Recently, association between polymorphisms of GSTT1 GSTM1 and susceptibility to BPD was reported (Mohammadynejad et al., 2011). However, there are no data on the association between GSTZ1 polymorphisms and BPD risk. Therefore, here we investigated the association between three genetic polymorphisms of Glu32Lys (rs.7975), Gly42Arg (rs.7972) and G-1002A in the promoter region of GSTZ1 and susceptibility to BPD.

Section snippets

Participants

A detailed description of the study subjects has been reported in our previous report (Mohammadynejad et al., 2011). We lost DNA samples of two subjects. Therefore, we include 228 (169 males, 59 females) in-patients with BPD and 234 (177 males, 57 females) healthy blood donors in the analysis. Patients and control subjects were unrelated Iranian/Muslims (Caucasian). Informed consent was obtained from each subject before the study. Patients were stratified according to their age at onset into

Results and Discussion

Table 1 shows the genotypic frequencies of the study polymorphisms in cases and controls. Control subjects for the genotypic frequencies of three polymorphisms were in Hardy-Weinberg equilibrium (for Glu32Lys: χ² = 0.766, d.f. = 1, P = 0.381; for Gly42Arg: χ² = 0.104., d.f. = 1, P = 748; for G-1002A: χ² = 0.171, df = 1, P = 0.679). The prevalences of 32Lys, 42Arg and -1002A alleles in our control samples were similar to those reported Caucasian populations (Blackburn et al., 2000, Fang et al., 2006, Olshan et

Acknowledgements

The authors are indebted to the participants for their close cooperation. This study was supported by Shiraz University.

References (20)

A.C. Andreazza et al.
Oxidative stress markers in bipolar disorder: a meta-analysis
Journal of Affective Disorders
(2008)
J.M. Fernandez-Canon et al.
Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue
Journal of Biological Chemistry
(1998)
S. Harada et al.
Glutathione S-transfearse M1 gene deletion may be associated with susceptibility to certain forms of schizophrenia
Biochemical and Biophysical Research Communications
(2001)
P. Mohammadynejad et al.
Bipolar disorder and polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1)
Psychiatry Research
(2011)
S. Nafissi et al.
Association between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to schizophrenia
Psychiatry Research
(2011)
A.F. Olshan et al.
Preliminary examination of polymorphisms of GSTM1, GSTT1, and GSTZ1 in relation to semen quality
Mutation Research
(2010)
C.U. Pae et al.
Association study between glutathione S-transferase P1 polymorphism and schizopherina in the Korean population
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(2003)
M. Saadat et al.
Genetic polymorphism of glutathione S-transferase T1: a candidate genetic modifier of individual susceptibility to schizophrenia
Psychiatry Research
(2007)
I.E. Andonova et al.
No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk
Breast Cancer Research and Treatment
(2010)
W.H. Berrettini
Genetics of psychiatric disease
Annual Review of Medicine
(2000)

There are more references available in the full text version of this article.

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Clinical physiology and pharmacology of GSTZ1/MAAI
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Herein I summarize the physiological chemistry and pharmacology of the bifunctional enzyme glutathione transferase zeta 1 (GSTZ1)/ maleylacetoacetate isomerase (MAAI) relevant to human physiology, drug metabolism and disease. MAAI is integral to the catabolism of the amino acids phenylalanine and tyrosine. Genetic or pharmacological inhibition of MAAI can be pathological in animals. However, to date, no clinical disease consequences are unequivocally attributable to inborn errors of this enzyme. MAAI is identical to the zeta 1 family isoform of GST, which biotransforms the investigational drug dichloroacetate (DCA) to the endogenous compound glyoxylate. DCA is a mechanism-based inhibitor of GSTZ1 that significantly reduces its rate of metabolism and increases accumulation of potentially harmful tyrosine intermediates and of the heme precursor δ-aminolevulinic acid (δ-ALA). GSTZ1 is most abundant in rodent and human liver, with its concentration several fold higher in cytoplasm than in mitochondria. Its activity and protein expression are dependent on the age of the host and the intracellular level of chloride ions. Gene association studies have linked GSTZ1 or its protein product to various physiological traits and pathologies. Haplotype variations in GSTZ1 influence the rate of DCA metabolism, enabling a genotyping strategy to allow potentially safe, precision-based drug dosing in clinical trials.
Proof-of-concept study of a multi-gene risk score in adolescent bipolar disorder
2020, Journal of Affective Disorders
Few studies have examined multiple genetic variants concurrently for the purpose of classifying bipolar disorder (BD); the literature among youth is particularly sparse. We selected 35 genetic variants, previously implicated in BD or associated characteristics, from which to identify the most robustly predictive group of genes.
215 Caucasian adolescents (114 BD and 101 healthy controls (HC), ages 13–20 years) were included. Psychiatric diagnoses were determined based on semi-structured diagnostic interviews. Genomic DNA was extracted from saliva for genotyping. Two models were used to calculate a multi-gene risk score (MGRS). Model 1 used forward and backward regressions, and model 2 used a PLINK generated method.
In model 1, GPX3 rs3792797 was significant in the forward regression, DRD4 exonIII was significant in the backward regression; IL1β rs16944 and DISC1 rs821577 were significant in both the forward and backward regressions. These variants are involved in dopamine neurotransmission; inflammation and oxidative stress; and neuronal development. Model 1 MGRS did not significantly discriminate between BD and HC. In model 2, ZNF804A rs1344706 was significantly associated with BD; however, this association did not predict diagnosis when entered into the weighted model.
This study was limited by the number of genetic variants examined and the modest sample size.
Whereas regression approaches identified four genetic variants that significantly discriminated between BD and HC, those same variants no longer discriminated between BD and HC when computed as a MGRS. Future larger studies are needed evaluating intermediate phenotypes such as neuroimaging and blood-based biomarkers.
Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder - Gender and obesity effects
2015, Journal of Affective Disorders
Citation Excerpt :
In contrast to the reduced TAC, the level of the important antioxidative enzyme GST was found to be increased in our BD cohort as compared to the normal ranges. Even though gene association studies point towards an influence of GST in BD (Hoogendoorn et al., 2004; Rezaei et al., 2012; Rodriguez-Santiago et al., 2010), we did not find significant differences in GST levels between BD and controls. Nevertheless, anthropometric parameters correlated positively with GST in male subjects of the whole cohort.
Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS).
Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m²], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS.
The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28).
Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.
Identification of a Novel Target Implicated in Chronic Obstructive Sleep Apnea-Related Atrial Fibrillation by Integrative Analysis of Transcriptome and Proteome
2023, Journal of Inflammation Research
Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder
2022, Genes
Differences and Similarities in Attentional Bias between Patients with Bipolar II Disorder and Borderline Personality Disorder
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Psychiatry Research

Abstract

Introduction

Section snippets

Participants

Results and Discussion

Acknowledgements

References (20)

Oxidative stress markers in bipolar disorder: a meta-analysis

Journal of Affective Disorders

Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue

Journal of Biological Chemistry

Glutathione S-transfearse M1 gene deletion may be associated with susceptibility to certain forms of schizophrenia

Biochemical and Biophysical Research Communications

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

Psychiatry Research

Association between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to schizophrenia

Psychiatry Research

Preliminary examination of polymorphisms of GSTM1, GSTT1, and GSTZ1 in relation to semen quality

Mutation Research

Association study between glutathione S-transferase P1 polymorphism and schizopherina in the Korean population

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Genetic polymorphism of glutathione S-transferase T1: a candidate genetic modifier of individual susceptibility to schizophrenia

Psychiatry Research

No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk

Breast Cancer Research and Treatment

Genetics of psychiatric disease

Annual Review of Medicine

Cited by (12)

Clinical physiology and pharmacology of GSTZ1/MAAI

Proof-of-concept study of a multi-gene risk score in adolescent bipolar disorder

Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder - Gender and obesity effects

Identification of a Novel Target Implicated in Chronic Obstructive Sleep Apnea-Related Atrial Fibrillation by Integrative Analysis of Transcriptome and Proteome

Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

Differences and Similarities in Attentional Bias between Patients with Bipolar II Disorder and Borderline Personality Disorder

Brief reportAssociation between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder

Abstract

Introduction

Section snippets

Participants

Results and Discussion

Acknowledgements

Journal of Affective Disorders

Journal of Biological Chemistry

Biochemical and Biophysical Research Communications

Psychiatry Research

Psychiatry Research

Mutation Research

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Psychiatry Research

No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk

Breast Cancer Research and Treatment

Genetics of psychiatric disease

Annual Review of Medicine

Brief report
Association between three genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to bipolar disorder