Glutathione S-Transferase M1, &lt;i&gt;GSTT1&lt;/i&gt; and &lt;i&gt;GSTP1&lt;/i&gt; Genetic Polymorphisms and the Risk of Age-Related Macular Degeneration

Güven, Mehmet; Görgün, Ebru; Ünal, Mustafa; Yenerel, Melda; Batar, Bahadır; Küçümen, Beril; Dinç, Umut Aslı; Güven, Gülgün S.; Ulus, Tümer; Yüksel, Adnan

doi:10.1159/000321940

Cited by 27 publications

(18 citation statements)

References 66 publications

(53 reference statements)

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“…Hypomethylation of the IL-17RC promoter exists in monozygotic twins with discordant disease corresponding to increased mRNA and protein expression in AMD macular lesions (Park et al, 2012; Wei et al, 2012). Hypermethylation of the AMD-associated glutathione S-transferase isoform mu1 (GSTM1) and mu5 (GSTM5) corresponding with reduced expression (Guven et al, 2011; Hunter et al, 2012) has also been reported in AMD patients. In mouse RPE, microsomal glutathione S-transferase (MGST1) has been shown to decrease in expression as a function of age to almost undetectable levels by 18 months (Maeda et al, 2005).…”

Section: The Aging Paradigm In Amdmentioning

confidence: 99%

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Ardeljan

Chan

2013

Progress in Retinal and Eye Research

212

176

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Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD.

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Section: The Aging Paradigm In Amdmentioning

confidence: 99%

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Ardeljan

Chan

2013

Progress in Retinal and Eye Research

212

176

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“…This gene is particularly of interest because a growing body of clinical and experimental data strongly implicate oxidative stress as a threat to the structural and functional integrity of the RPE (Cai et al, 2000;Plafker et al, 2012). GST polymorphisms may be associated with an increased risk for the development of primary openangle glaucoma, age-related macular degeneration (AMD), and age-related cataract (ARC) (Gü ven et al, 2011;Jiang et al, 2012;Juronen et al, 2000;Othman et al, 2012). The precise link between GSTT1 and LCA pathology is unknown, but its downregulation in both LCA-NSC and LCA-RPE cells might suggest it plays a role (along with TRIM61 and ZNF558) in the mechanisms underlying the LCA phenotype through interactions with other unknown proteins and thus deserves further examination.…”

mentioning

confidence: 99%

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Lustremant

Habeler

Plancheron

et al. 2013

Cellular Reprogramming

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Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA) and to model this type of LCA for drug screening. Fibroblasts from two unrelated clinically identified patients with a yet undetermined gene mutation were reprogrammed to pluripotency by retroviral transduction. These human induced pluripotent stem cells (hiPSCs) were differentiated into neural stem cells (NSCs) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome-wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip(®), comparing LCA-hiPSCs derivatives to controls. A genomic search for alteration in all genes known to be involved in LCA revealed a common polymorphism on the GUCY2D gene, referenced as the LCA type I (OMIM *600179 and #204000), but the causative gene remained unknown. The hiPSCs expressed the key pluripotency factors and formed embryoid bodies in vitro containing cells originating from all three germ layers. They were successfully differentiated into NSC and RPE cells. One gene, NNAT, was upregulated in LCA cell populations, and three genes were downregulated, GSTT1, TRIM61 and ZNF558, with potential correlates for molecular mechanisms of this type of LCA, in particular for protein degradation and oxidative stress. The two LCA patient-specific iPSC lines will contribute to modeling LCA phenotypes and screening candidate drugs.

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“…Accordingly, we performed sample cohort studies using gCN analysis to see if copy number variations of GSTM1 and GSTM5 could be an independent risk factor for AMD. Guven et al reported GSTM1 homozygous null (determined by PCR from peripheral leukocytes) associated with AMD and dry AMD (after subtype stratification) in a Turkish population (34). Our results failed to show such an association for AMD or with AMD subtype stratification (e.g., early vs. late, neovascular or atrophic AMD), (data not shown).…”

Section: Discussionmentioning

confidence: 99%

GSTM1andGSTM5Genetic Polymorphisms and Expression in Age-Related Macular Degeneration

Hunter

Smit-McBride

Anderson

et al. 2015

Current Eye Research

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Purpose Previously, two cytosolic antioxidant enzymes, Glutathione S-transferase Mu 1 (GSTM1) and Mu 5 (GSTM5), were reduced in retinas with Age-related Macular Degeneration (AMD). This study compared genomic copy number variations (gCNV) of these two antioxidant enzymes in AMD vs. controls. Methods Genomic copy number (gCN) assays were performed using Taqman Gene Copy Number Assays (Applied Biosystems) in technical quadruplicate for both GSTM1 and GSTM5. Peripheral leukocyte RNA levels were compared to controls in technical triplicates. Statistical comparisons were performed in SAS v9.2 (SAS Institute Inc. Cary, NC). Results A large percentage of patients in both AMD and age-matched control groups had no copies of GSTM1 (0/0). The mean gCN of GSTM1 was 1.40 (range 0 – 4) and 1.61 (range 0 – 5) for AMD and control, respectively (p = 0.29). A greater percentage of control patients had > 3 gCNs of GSTM1 compared to AMD, respectively (15.3% vs. 3.0%, p = 0.004). The gCN of GSTM5 was 2 in all samples except one control sample. The relative quantification of GSTM1 and GSTM5 mRNA from peripheral blood leukocytes in patients showed significant differences in relative expression in AMD vs. control (p < 0.05). Peripheral blood leukocyte mRNA and gCN were not significantly correlated (p = 0.27). Conclusion Since high copy numbers of GSTM1 are found more frequently in controls than in AMD, it is possible that high copy number leads to increased retinal antioxidant defense. Genomic polymorphisms of GSTM1 and GSTM5 do not significantly affect the peripheral blood leukocyte mRNA levels.

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Glutathione S-Transferase M1, <i>GSTT1</i> and <i>GSTP1</i> Genetic Polymorphisms and the Risk of Age-Related Macular Degeneration

Cited by 27 publications

References 66 publications

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Aging is not a disease: Distinguishing age-related macular degeneration from aging

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

GSTM1andGSTM5Genetic Polymorphisms and Expression in Age-Related Macular Degeneration

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