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      Is the GSTM1 null polymorphism a risk factor in Primary Open Angle Glaucoma?

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          Abstract

          Purpose

          To investigate the association of glutathione S-transferase ( GST) GSTM1, GSTT1, and GSTP1 genes with the risk of primary open angle glaucoma (POAG) and clinical features of the disease.

          Methods

          We conducted a case-control study that included 87 Brazilian patients with POAG and 85 healthy controls matched for age, ethnicity, and sex, whose blood samples were genotyped for polymorphisms in GST genes using polymerase chain reaction (PCR) based methods.

          Results

          The GSTM1 null polymorphism was significantly more common in the POAG than in the controls group (OR: 2.1, 95% CI: 1.13–3.9; p=0.018). The combined GSTM1 null/ GSTT1+ genotype and GSTM1 null/ GSTP1 Ile/Val or Val/Val was more prevalent in POAG patients, being a risk factor for POAG (OR: 2.4, 95% CI: 1.16–4.9; p=0.016 and OR: 2.7, 95% CI: 1.07–6.74; p=0.033, respectively). The GSTM1 null/ GSTT1+ genotype were associated with higher levels of IOP of both eyes and with more severe defect of the right eye optic nerve. The GSTM1 null/ GSTP1 Ile/Val or Val/Val genotypes were associated with higher levels of IOP and more advanced defect of the right eye optic nerve and visual field.

          Conclusions

          We demonstrate that GSTM1 null polymorphism is associated with POAG in the Brazilian population.

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          Glutathione transferases.

          John Hayes, Jack U. Flanagan, Ian R Jowsey (2005)
          This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
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            The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators.

            (2000)
            To investigate the association between control of intraocular pressure after surgical intervention for glaucoma and visual field deterioration. In the Advanced Glaucoma Intervention Study, eyes were randomly assigned to one of two sequences of glaucoma surgery, one beginning with argon laser trabeculoplasty and the other trabeculectomy. In the present article we examine the relationship between intraocular pressure and progression of visual field damage over 6 or more years of follow-up. In the first analysis, designated Predictive Analysis, we categorize 738 eyes into three groups based on intraocular pressure determinations over the first three 6-month follow-up visits. In the second analysis, designated Associative Analysis, we categorize 586 eyes into four groups based on the percent of 6-month visits over the first 6 follow-up years in which eyes presented with intraocular pressure less than 18 mm Hg. The outcome measure in both analyses is change from baseline in follow-up visual field defect score (range, 0 to 20 units). In the Predictive Analysis, eyes with early average intraocular pressure greater than 17.5 mm Hg had an estimated worsening during subsequent follow-up that was 1 unit of visual field defect score greater than eyes with average intraocular pressure less than 14 mm Hg (P =.002). This amount of worsening was greater at 7 years (1.89 units; P <.001) than at 2 years (0.64 units; P =.071). In the Associative Analysis, eyes with 100% of visits with intraocular pressure less than 18 mm Hg over 6 years had mean changes from baseline in visual field defect score close to zero during follow-up, whereas eyes with less than 50% of visits with intraocular pressure less than 18 mm Hg had an estimated worsening over follow-up of 0.63 units of visual field defect score (P =.083). This amount of worsening was greater at 7 years (1.93 units; P <.001) than at 2 years (0.25 units; P =.572). In both analyses low intraocular pressure is associated with reduced progression of visual field defect, supporting evidence from earlier studies of a protective role for low intraocular pressure in visual field deterioration.
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              The role of oxidative stress in glaucoma.

              Alberto Izzotti, Alessandro Bagnis, Sergio Saccà (2006)
              DNA damage is related to a variety of degenerative diseases such as cancer, atherosclerosis and neurodegenerative diseases, depending on the tissue affected. Increasing evidence indicates that reactive oxygen species (ROS) play a key role in the pathogenesis of primary open angle glaucoma (POAG), the main cause of irreversible blindness worldwide. Oxidative DNA damage is significantly increased in the ocular epithelium regulating aqueous humor outflow, i.e., the trabecular meshwork (TM), of glaucomatous patients compared to controls. The pathogenic role of ROS in glaucoma is supported by various experimental findings, including (a) resistance to aqueous humor outflow is increased by hydrogen peroxide by inducing TM degeneration; (b) TM possesses remarkable antioxidant activities, mainly related to superoxide dismutase-catalase and glutathione pathways that are altered in glaucoma patients; and (c) intraocular-pressure increase and severity of visual-field defects in glaucoma patients parallel the amount of oxidative DNA damage affecting TM. Vascular alterations, which are often associated with glaucoma, could contribute to the generation of oxidative damage. Oxidative stress, occurring not only in TM but also in retinal cells, appears to be involved in the neuronal cell death affecting the optic nerve in POAG. The highlighting of the pathogenic role of ROS in POAG has implications for the prevention of this disease as indicated by the growing number of studies using genetic analyses to identify susceptible individuals and of clinical trials testing the efficacy of antioxidant drugs for POAG management.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Vis
                Journal ID (publisher-id): MV
                Title: Molecular Vision
                Publisher: Molecular Vision
                ISSN (Electronic): 1090-0535
                Publication date Collection: 2011
                Publication date (Electronic): 23 June 2011
                Volume: 17
                Pages: 1679-1686
                Affiliations
                [1 ]Universidade Estadual de Santa Cruz, Departamento de Ciências da Saúde, Laboratório de Farmacogenômica e Epidemiologia Molecular (LAFEM), Ilhéus, Bahia, Brazil
                [2 ]Universidade Federal de Sergipe - Campus de Lagarto, Laboratório de Genética, São Cristovão, Sergipe, Brazil
                Author notes
                Correspondence to: Fabricio Rios-Santos, Pharmacogenomic Genetic and Molecular Epidemiology Laboratory (LAFEM), Departamento de Ciências da Saúde, Universidade Estadual de Santa Cruz (UESC), Rod. Ilhéus – Itabuna (Km16), Salobrinho, Bahia – Brasil, 45662-900. Phone: +55-73-36805327; FAX: +55-73-36805114; email: fabriciorios@ 123456yahoo.com
                Article
                Publisher ID: 186 Publisher ID: 2011MOLVIS0111
                PMC ID: 3130720
                PubMed ID: 21738397
                SO-VID: d7f56792-a571-43d5-8010-b52da6f80b03
                Copyright © Copyright © 2011 Molecular Vision.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 12 March 2011
                Date accepted : 16 June 2011
                Categories
                Subject: Research Article
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                corr-author Rios-Santos

                ScienceOpen disciplines: Vision sciences
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                ScienceOpen disciplines: Vision sciences

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