| 1 | Psychiatr. Genet. 2004 Sep 14: 177-80 |
|---|---|
| PMID | 15318035 |
| Title | No association between the Pro197Leu polymorphism in the glutathione peroxidase (GPX1) gene and schizophrenia. |
| Abstract | Oxidative stress such as free radical-mediated neuronal dysfunction may be involved in the pathophysiology of schizophrenia. The human glutathione peroxidase (GPX1) is a selenium-dependent enzyme, which plays an important role in the detoxification of free radicals. We therefore hypothesized that the GPX1 gene, which is located on chromosome 3p21.3, may be involved in the pathophysiology of schizophrenia. The aim of this study is to examine whether a potentially functional polymorphism, a proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) of the human GPX1 gene, is associated with susceptibility to schizophrenia. We genotyped the Pro197Leu polymorphism in a total of 113 nuclear families that had a proband with schizophrenia. Genetic association was tested using the transmission disequilibrium test (TDT), the sib transmission disequilibrium test (STDT), and the family-based association test (FBAT). The minor allele (Leu) frequency was calculated to be 0.282. We could not find significant transmission disequilibrium of the alleles for the Pro197Leu polymorphism in the GPX1 gene in association with the presence of schizophrenia in our family sample (TDT, chi2=0.03, degrees of freedom=1, P=0.86; combined TDT-STDT, Z'=-0.052, P=0.47; FBAT, Z=0.000, P=1.000). The results of this study suggest that the GPX1 polymorphism is unlikely to be associated with susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Psychiatry Res 2006 Feb 141: 123-8 |
| PMID | 16413612 |
| Title | Genetic association analysis of the glutathione peroxidase (GPX1) gene polymorphism (Pro197Leu) with tardive dyskinesia. |
| Abstract | A possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in [Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Progress in Neurobiology 61, 525-541.]). Long-term administration of neuroleptics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a possible functional polymorphism of the human glutathione peroxidase (GPX1) gene (an important antioxidant enzyme) was studied in 68 chronic treatment-refractory patients with schizophrenia. A proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) in the GPX1 gene was genotyped. No significant difference in total Abnormal Involuntary Movements Scale (AIMS) scores was observed among patients in the three genotype groups. Moreover, no significant differences in genotype or allele frequencies were observed between subjects with and without TD. Our results suggest that the GPX1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jan 150B: 86-94 |
| PMID | 18449862 |
| Title | Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. |
| Abstract | Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jan 150B: 86-94 |
| PMID | 18449862 |
| Title | Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. |
| Abstract | Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Hum Psychopharmacol 2009 Dec 24: 676-9 |
| PMID | 19946932 |
| Title | Lack of association of GPX1 and MnSOD genes with symptom severity and response to clozapine treatment in schizophrenia subjects. |
| Abstract | Abnormal activities of critical antioxidant enzymes and other indices of lipid peroxidation in plasma and red blood cells were detected in patients with schizophrenia. Other results have shown that oxidative stress may be modulated by clozapine. Based on that and some studies already found different clinical relations between reactive oxygen species and negative and positive symptoms, we evaluated association between clinical response and the polymorphism in the human glutathione peroxidase (GPX1) (Pro200Leu, rs1050450) and manganese SOD (MNSOD) (Ala16Val, rs4880) gene in 216 clozapine-treated patients with schizophrenia. No association was found with these two functional polymorphisms and clozapine response and symptom change after 6 months. No correlations were found between positive/negative symptoms score and both polymorphisms. Our results present that GPX1 (Pro200Leu) and MNSOD (Ala16Val) polymorphisms seem do not play a central role in the clozapine response, although studies in larger and independent samples are necessary to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | J Biochem Pharmacol Res 2013 Dec 1: 228-235 |
| PMID | 24494173 |
| Title | Homozygous Deletion of Glutathione Peroxidase 1 and Aldehyde Dehydrogenase 1a1 Genes Is Not Associated with Schizophrenia-Like Behavior in Mice. |
| Abstract | Much evidence suggests that oxidative stress plays a role in schizophrenia pathogenesis. Major oxidative stress sources include hydrogen peroxide and biogenic aldehydes that are mainly cleared in vivo by glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), respectively. Both enzymes are richly expressed in brain. schizophrenia patients have significantly increased plasma levels of malondialdehyde and glutathione, combined with decreased GPX activity and ALDH1 mRNA levels in the ventral tegmental area. Absence of Aldh1a1 (murine homolog of ALDH1) gene causes increased basal extracellular dopamine concentrations, a common characteristic of schizophrenia. Studies investigating association between gene polymorphisms of GPX1 (the most abundant form of GPX) or ALDH1A1 with schizophrenia also have not clearly demonstrated whether ALDH1A1 or GPX1 is involved in pathogenesis of schizophrenia. To investigate possible contributions of ALDH and GPX to pathological behaviors associated with schizophrenia, we generated mice with both Aldh1a1 and GPX1 gene deletions (KO). Aldh1a1/GPX1 KO and wild type (WT) mice had similar number of novel entry and alteration in Y-maze test, suggesting no cognition deficit in KO. Furthermore, KO and WT displayed similar social interaction and novelty preferences in three chambered tests. Overall, KO and WT had similar activity levels, as indicated by their entries in the Y-maze and sociability tests. Furthermore both genotypes buried a similar percentage of marbles in a 30 min marble-burying task. In summary, homozygous deletion of GPX1 and Aldh1a1 genes was not associated with schizophrenia-like behavioral phenotypes including anxiety, hyperactivity, cognitive deficit or social disability. Our findings suggest that constitutive absence of these genes alone is unlikely to give rise to common behavioral schizophrenia symptoms. However, these mice may be highly sensitive to oxidative challenges during critical stages of prenatal or juvenile brain development. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Neurochem. Res. 2013 Feb 38: 433-42 |
| PMID | 23212700 |
| Title | Association of SOD2, GPX1, CAT, and TNF genetic polymorphisms with oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms in schizophrenia. |
| Abstract | There is a growing body of evidence confirming the involvement of oxidative stress and inflammation in pathogenesis of schizophrenia. Inter-individual variation in antioxidant capacity caused by different genetic profile could potentially influence patient's susceptibility to oxidative damage. In this study we evaluated the polymorphisms of manganese superoxide dismutase SOD2Val16Ala, glutathione peroxidase GPX1Pro200Leu, catalase CAT-262C>T and CATc.66+78C>T, and tumour necrosis factor-alpha TNF-308G>A by assessing their association with biomarkers of oxidative stress, neurochemistry, psychopathology of schizophrenia and extrapyramidal symptoms in Caucasian schizophrenia patients treated with haloperidol depot. TNF-308G>A was associated with the increased risk of parkinsonism. No major role of polymorphism of SOD2Val16Ala, CAT-262C>T nor GPX1Pro200Leu in psychopathology of schizophrenia or extrapyramidal symptoms was observed. SOD2Val16Ala polymorphism was associated with dopamine plasma concentration and blood concentration ratio between reduced and oxidised form of glutathione, while GPX1Pro200Leu was related with concentration of reduced glutathione. CATc.66+78C>T was associated with noradrenaline plasma concentration and PANSS negative score. PANSS positive and general scores, were associated with the increased risk of tardive dyskinesia. PANSS positive, negative, and general scores, and GAF score were all associated with the increased risk of akathisia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Biomed Res Int 2015 -1 2015: 853573 |
| PMID | 26682223 |
| Title | Significance of Polymorphisms and Expression of Enzyme-Encoding Genes Related to Glutathione in Hematopoietic Cancers and Solid Tumors. |
| Abstract | Antioxidant compounds such as glutathione and its enzymes have become the focus of attention of medical sciences. Glutathione, a specific tripeptide, is involved in many intercellular processes. The glutathione concentration is determined by the number of GAG repeats in gamma-glutamylcysteine synthetase. GAG polymorphisms are associated with an increased risk of schizophrenia, berylliosis, diabetes, lung cancer, and nasopharyngeal tumors. Cancer cells with high glutathione concentration are resistant to chemotherapy treatment. The oxidized form of glutathione is formed by glutathione peroxidases (GPXs). The changes in activity of GPX1, GPX2, and GPX3 isoforms may be associated with the development of cancers, for example, prostate cancer or even colon cancer. Detoxification of glutathione conjugates is possible due to activity of glutathione S-transferases (GSTs). Polymorphisms in GSTM1, GSTP1, and GSTO1 enzymes increase the risk of developing breast cancer and hepatocellular carcinoma. Gamma-glutamyl transpeptidases (GGTs) are responsible for glutathione degradation. Increased activity of GGT correlates with adverse prognosis in patients with breast cancer. Studies on genes encoding glutathione enzymes are continued in order to determine the correlation between DNA polymorphisms in cancer patients. |
| SCZ Keywords | schizophrenia, schizophrenic |