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      Association of TNFA –308 G/A and TNFRI +36 A/G Gene Polymorphisms with Glaucoma

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          Abstract

          Objective: TNF-α is one of the most important factors recognized in the pathogenesis of open-angle glaucoma. Therefore, the association of single nucleotide polymorphisms in the TNFRI gene and the promoter region of the TNFA gene with glaucoma susceptibility was investigated in the present study. Method: In total, 223 patients with glaucoma and 202 unrelated controls were genotyped by allele-specific oligonucleotide PCR and PCR- restriction fragment length polymorphism to determine TNFA –308 G/A and TNFRI +36 A/G polymorphisms, respectively. Results: In contrast to TNFRI polymorphisms, the genotypes of TNFA –308 G/A polymorphisms showed a significant difference between patients and controls (p = 0.0025). Of interest, the distribution of TNFA genotypes was significantly different between patients with primary open-angle glaucoma (p = 0.001) or pseudoexfoliative glaucoma (p = 0.001) and controls, while no difference was found when chronic angle-closure glaucoma patients were compared to controls (p = 0.72). Conclusion: In line with studies showing the role of TNF-α in open-angle glaucoma, the results of the present study showed that inheritance of the high producer TNFA –308 A allele might be a susceptibility factor for the development of open-angle glaucoma.

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          Most cited references 17

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          Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma.

          Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-alpha (TNF-alpha) may contribute to the disease process, although its role in vivo and its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-alpha, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-alpha injections in normal mice mimicked these effects. Conversely, an anti-TNF-alpha-neutralizing antibody or deleting the genes encoding TNF-alpha or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-alpha provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-alpha signaling or inflammation, therefore, may be helpful in treating glaucoma.
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            TNF-alpha signaling in glaucomatous neurodegeneration.

            Growing evidence supports the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of neurodegeneration in glaucoma. Glial production of TNF-alpha is increased, and its death receptor is upregulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. In addition to direct neurotoxicity, potential interplay of TNF-alpha signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to spreading neuronal damage by secondary degeneration. Opposing these cell death-promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-alpha as best exemplified by differential responses of RGCs and glia. This review focuses on the present evidence supporting the involvement of TNF-alpha signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.
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              Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF- beta production

               EH Weiss,  G. Messer,  MC Jung (1991)
              Since a dysregulated synthesis of tumor necrosis factor alpha (TNF- alpha) may be involved in the pathogenesis of autoimmune diseases, it was of interest to precisely locate the recently reported NcoI restriction fragment length polymorphism (RFLP) of the TNF-alpha region. However, by mapping of 56.8 kb of overlapping cosmid clones and direct sequencing, we could localize the polymorphic NcoI restriction site within the first intron of the TNF-beta gene and not in the TNF- alpha gene. To study whether regulatory mechanisms are affected by this polymorphism, we analyzed the TNF-alpha/TNF-beta production of phytohemagglutinin-stimulated peripheral blood mononuclear cells of individuals homozygous for the TNF-beta NcoI RFLP by ELISA and concomitant Northern blot analysis. On days 2-4 after stimulation with mitogen, the TNFB*1 allele corresponding to a 5.3-kb NcoI fragment presented with a significantly higher TNF-beta response. A mRNA analysis demonstrated that higher protein levels of TNF-beta correlate also with increased amounts of TNF-beta transcripts. No allelic association was found in respect to TNF-alpha production. To further investigate a possible allelic influence on transcription, we determined the DNA sequence of 2 kb of the 5' portion of our cloned TNFB*2 allele and compared it with the available TNF-beta sequences. By computer-aided recognition motif search of DNA binding factors, we report putative binding sites conserved between mouse and man in the 5' flanking region as well as in intron 1 of the TNF-beta gene, found also in other cytokine promoter sequences. In addition, by polymerase chain reaction amplification and sequencing of 740 bp of the 5' part of TNF- beta of individuals typed homozygously for the NcoI RFLP, we could show that amino acid position 26 is conserved as asparagine in the TNFB*1 and as threonine in the TNFB*2 sequence. A previously reported, EcoRI RFLP in the 3' untranslated region of TNF-beta does not segregate with either of the two alleles. Thus, four TNFB alleles can be defined at the DNA level.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2009
                November 2009
                24 June 2009
                : 42
                : 3
                : 118-124
                Affiliations
                aDepartment of Ophthalmology, bDepartment of Immunology and cAutoimmune Diseases Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
                Article
                226108 Ophthalmic Res 2009;42:118–124
                10.1159/000226108
                19556827
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 3, References: 29, Pages: 7
                Categories
                Original Paper

                Vision sciences, Ophthalmology & Optometry, Pathology

                Polymorphism, Tumor necrosis factor, Glaucoma

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