Elsevier

Survey of Ophthalmology

Volume 60, Issue 4, July–August 2015, Pages 310-326
Survey of Ophthalmology

Major review
The interactions of genes, age, and environment in glaucoma pathogenesis

https://doi.org/10.1016/j.survophthal.2015.01.004Get rights and content

Abstract

Glaucoma, a progressive degenerative condition that results in the death of retinal ganglion cells, is one of the leading causes of blindness, affecting millions worldwide. The mechanisms underlying glaucoma are not well understood, although years of studies have shown that the largest risk factors are elevated intraocular pressure, age, and genetics. Eleven genes and multiple loci have been identified as contributing factors. These genes act by a number of mechanisms, including mechanical stress, ischemic/oxidative stress, and neurodegeneration.

We summarize the recent advances in the understanding of glaucoma and propose a unified hypothesis for glaucoma pathogenesis. Glaucoma does not result from a single pathological mechanism, but rather a combination of pathways that are influenced by genes, age, and environment. In particular, we hypothesize that, in the presence of genetic risk factors, exposure to environment stresses results in an earlier age of onset for glaucoma. This hypothesis is based upon the overlap of the molecular pathways in which glaucoma genes are involved. Because of the interactions between these processes, it is likely that there are common therapies that may be effective for different subtypes of glaucoma.

Section snippets

How do we define glaucoma?

Glaucoma, a progressive degenerative condition of the retina that results in the death of the retinal ganglion cells (RGCs), eventually causing blindness. It is a leading cause of irreversible blindness worldwide. It is believed that 79.6 million people will be affected by glaucoma by the year 2020, 10% of whom will be bilaterally blind.182 The pathology of glaucoma is not entirely elucidated,163 although it is known that there are multiple risk factors such as genes, ethnicity, age, and

Glaucoma subtypes

There are a number of types of glaucoma, broadly described as: primary, congenital, juvenile, or secondary glaucoma. Primary glaucoma occurs without syndromic features, whereas secondary glaucoma often presents as a result of an underlying anterior chamber defects that confer a 50% chance of developing glaucoma.101 These defects include keratolenticular adhesions as is seen in Peters anomaly (OMIM 604229) or iris hypoplasia as seen in Axenfeld-Rieger syndrome (OMIM 602482).

The subtypes of

Glaucoma as a neurodegenerative disorder

Glaucoma is characterized by progressive damage to RGCs, leading to blindness. RGC death, axonal loss, and damage to surrounding microglia classify glaucomatous optic neuropathy among other neurodegenerative diseases such as Parkinson disease and Alzheimer disease (AD).104 As in other neurodegenerative disorders, POAG can be divided to early onset and late onset forms, both of which are thought to result from the interaction of genetic and environmental factors.94, 139

Reports of overlaps

Environmental factors in glaucoma pathogenesis

Several environmental factors are generally considered to act within central glaucomatous mechanisms by causing IOP increase and contributing to RGC death.247 The study of environmental factors on glaucoma pathogenesis is evolving rapidly, yet results are conflicting.

Smoking has been investigated since the 1970s as a glaucoma contributing factor, though findings have been contradictory.142 Among recent studies, Kang et al found an interesting interaction between genetic risk factors and smoking.

Genes associated with glaucoma

Glaucoma can arise from hereditary and non-hereditary factors.79, 186 Hereditary forms of glaucoma are considered, as are all common complex diseases, to result from environmental, gene–environment, and/or epistatic (gene–gene) interactions; glaucoma, however, can also be inherited as a Mendelian trait as is seen in patients with MYOC mutations.187, 207 Recognizing that identifying the causes of inherited glaucoma should provide insight into the pathogenesis of all glaucoma phenotypes, major

Mechanisms underlying glaucoma

A complete understanding of glaucoma pathogenesis has not yet been achieved, although there are a number of hypotheses. One is that mechanical stress applied by the increased IOP causes death of the RGCs.60, 254 Others have suggested that elevated IOP causes an increase in the accumulation of reactive oxygen species (ROS) and the resultant oxidative damage causes death of the RGCs.15, 20, 87, 100, 114, 127, 129, 152, 218, 222, 258 These ideas, although distinct, are not necessarily exclusive

Glaucoma treatment

As indicated previously, current glaucoma therapies are directed at lowering IOP; however, it is clear that additional pathogenic mechanisms that are not related to elevated IOP have a significant role in glaucomatous optic neuropathy. Treatment with IOP-lowering agents such as prostaglandin analogues or beta-blockers (Table 2) alone have limited effect, as some patients continue to suffer from RGC death following IOP-lowering medications, whereas other patients have glaucoma despite normal IOP.

Conclusions

Glaucoma is a common form of neurodegeneration that is the leading cause of irreversible blindness in the world. Recent investigations are leading to new understanding of the mechanisms of glaucoma. In particular, it appears that genetic background risk factors combined with exposure to environment stresses results in earlier age of onset for glaucoma. New therapies, based upon this improved understanding of the factors involved and the molecular defects occurring within glaucoma patients, are

Literature search

We used three different search engines (PubMed, University of Alberta Library, and ScienceDirect) to identify papers for review. Search terms included glaucoma and genetics, glaucoma and genes, glaucoma review, glaucoma and drugs/therapies, glaucoma and environment, glaucoma and risk factors, glaucoma and excitotoxicity, glaucoma and neuroprotection, glaucoma and Alzheimer, glaucoma and neurodegeneration, retinal ganglion cell death and genetics. In addition, we obtained further references from

Disclosure

The authors declare no conflict of interest.

Acknowledgments

All work was supported by grant 119605 from the Canadian Institute for Health Research (MW). Trainees are supported by fellowships/scholarships from Alberta Health Services (MS), The Department of Medical Genetics, University of Alberta (MS, AR), and the Faculty of Medicine and Dentistry, University of Alberta (AR). We would also like to thank Mr. Tim Footz for his assistance in reviewing the content of this manuscript and editing of figures, and Dr. Ordan J. Lehmann for his expertise and

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