Major reviewThe interactions of genes, age, and environment in glaucoma pathogenesis
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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