**12. Concluding remarks**

the finding that XFS may be associated with geographic and climatic factors such as sun ex‐ posure and ambient temperature [89]. The mechanisms involved are not known at present. Retinal cell death, the most common pathophysiology of all forms of glaucoma involves many factors such as oxidative stress, mitochondrial dysfunction, excitotoxic damage, axo‐ nal transport failure, deprivation of neurotrophic factors and activation of intrinsic and ex‐ trinsic apoptotic signals [90-91]. Some of these could be modulated by epigenetic changes. In support of this is the finding that heavy smoking, exposure to pesticides and nutrient intake was significantly associated with POAG [92-94]. This suggests that the interaction between gene and environmental factors may play a role in the pathogenesis of glaucoma. Intrauter‐ ine exposure (obesity and diabetes), variable DNA methylation and environmental factors may also have profound influence on adult epigenetic status. Thus in general, epigenetic may provide an additional layer of important information on inherited as well as age-relat‐

**11. Pharmacogenetics and pharmacoepigenetics in glaucoma**

Adverse drug reactions (ADRs) and individual variations in drug response were well known in medicine. There are many systemic and other drugs that produce adverse effects in eye care [95-96]. For instance, many steroid drugs induce glaucoma in some patients [97]. Therefore, efficacy and safety are important aspects of initiation of any medication. Present‐ ly, there are no biochemical markers (proteins or genes) to predict which group of patients develops ADR and which group does not. Physicians in all medical branches have to make a guessing game to find out, which medication will work best for a given patient. This trialand error method is often inefficient. Now because of the advancement in genetics, physi‐ cians will have better opportunities to treat individual patients based on their genotype (Fig. 2). In order to understand the relationship between genes and inter-individual variations in drug response, two related fields namely pharmacogenetics and pharmacogenomics have been developed. They have taken massive studies on genetic personalization of drug re‐ sponse [98]. Some of the pharmacogenetic studies that are related to eye disorders including glaucoma have been discussed previously [99-100]. For instance, heterozygosity in N363S mutation in glucocorticoid receptor gene has been found to be associated with steroid in‐ duced ocular hypertension in Hungarian population although it may not be the major risk factor in the pathogenesis of elevated IOP. Similarly, a beta-adrenergic antagonist timolol has been used for the treatment of glaucoma. However, a topically administered eye drop may cause adverse cardiovascular and respiratory effects. Recent investigation of a single nucleotide polymorphism (SNP) in beta-adrenergic receptor suggests that this polymor‐ phism may be associated with positive clinical response to topical beta-blockers. In addition, R296C polymorphism in CYP 2D6 (cytochrome P450) gene may confer susceptibility to tim‐ olol induced bradycardia. Patients with CC genotype were unlikely to suffer from timolol induced bradycardia and those with TT genotype were found to suffer. Many studies ad‐ dress the pharmacology of several glaucoma medications but it is still not possible to ex‐ plain the variable IOP response to glaucoma drugs between patients [101] using their

ed eye disorders including glaucoma.

64 Glaucoma - Basic and Clinical Aspects

Epigenetic is an emerging field in ophthalmology. One benefit of understanding epigenetic changes is at the level of treatment. Epigenetic modifications are reversible. For instance, disease associated DNA methylation can be reversed by inhibitors such as adenosine or deoxycytidine. However, these reagents might become cytotoxic and may lead to a wide spread DNA hypome‐ thylation that may be resulting in and causing destabilization of genome. We need to develop less toxic inhibitors of DNA mythyltransferases. Similarly, inhibitors of histone deacetylase (HDAC) may have some therapeutic applications. For instance, HDAC inhibitors have been found to have protective effects in animal model of ischemia and optic nerve damage in the retina [71, 102-103]. At present IOP is the only modifiable risk factor for the prevention or progression of glaucoma and low IOP is associated with reduced progression of visual field defect [104-105]. Recent devel‐ opment on stem-cell therapy may be interesting. The initial results of clinical trials in patients us‐ ing stem-cell therapy showed some visual benefits with no sign of tumorigenicity [106-111]. Therefore, stem-cell therapy may be a promising approach to treat patients with retinal disease in the future. However, further research will be needed and an understanding of the role of epige‐ netics is also important to the success of the stem cell-based therapies [8]. In the future, studies will uncover the epigenetic mechanism contributing to glaucoma. A strong emphasis must be placed on epigenetics in the analysis of complex phenotypic variation. It may be necessary to de‐ velop a human methylation map to understand the difference in transcript expression. Epigenet‐ ic mechanisms in ophthalmology are truly exciting areas of research.

### **Glossary**

Apoptosis: genetically programmed cell death Chromatin : a complex of nucleic acids and proteins Euchromatin: a less condensed, mostly transcriptionally active chromatin Heterochromatin: a highly condensed chromatin Histones: small DNA binding proteins miRNA: short regulatory non-coding RNAs

### **Author details**

Barkur S. Shastry

Department of Biological Sciences, Oakland University, Rochester, MI, USA

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Department of Biological Sciences, Oakland University, Rochester, MI, USA

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**Chapter 5**

**Modern Aspects of Glaucoma Pathogenesis Local Factors**

**for Development of Primary Open-Angle Glaucoma**

**the Eye Membranes**

http://dx.doi.org/10.5772/55037

Additional information is available at the end of the chapter

A.A. Zilfyan

**1. Introduction**

nosed form.

**Associated with Impairment of Secretory Functions of**

The term "Glaucoma" integrates a wide range of eye diseases characterized by a diversity of clinical forms: mainly by the chronic course and rather unfavourable prognosis. Sufficient to mention that in developed countries the frequency of vision loss due to glaucoma is steadily

It is considered long-established that among various clinical-and-anatomical manifestations of the glaucomatous process the anterior open-angle glaucoma is the most frequently diag‐

The severity of course of anterior open-angle glaucoma and especially the unfavourable outcomes of the disease are mainly connected with those unsolvable problems faced by ophthalmologists at the study of pathogenesis of primary and secondary glaucomas. Precisely this circumstance is the "insurmountable" obstacle in pathogenetic therapy, thus limiting the entire complex of medical interventions within the early symptomatic therapy with underlying

To a known extent, the interpretation of aspects of pathogenesis in case of anterior open-angle glaucoma is connected to the fact that this type of glaucoma is rather frequently associated

At present the etiopathogenetic links engaged in induction and the course of anterior open-

and reproduction in any medium, provided the original work is properly cited.

© 2013 Zilfyan; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

at the level of 15-20% of the total number of all blind subjects [*Nesterov A.P., 2008*].

local application of hypotensive means aimed to decrease intraocular pressure.

angle glaucoma are conditionally divided into general and local ones.

with the cataract and pseudoexfoliative syndrome.


**Modern Aspects of Glaucoma Pathogenesis Local Factors for Development of Primary Open-Angle Glaucoma Associated with Impairment of Secretory Functions of the Eye Membranes**
