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Unraveling the genetics of glaucoma for potential therapies


By Cheryl Guttman Krader

Genetic testing to identify susceptibility for adult-onset primary open angle glaucoma (POAG) or pseudoexfoliation (PXF) glaucoma has a very limited role in clinical practice at this time, said Robert T. Chang, MD.

Watch as Robert Chang, MD, differentiates the fact from fiction in glaucoma genetics.


Dr. Chang cited a consensus recommendation from the 2014 American Academy of Ophthalmology Task Force on Genetic Testing. The group concluded that routine testing for genetically complex disorders, which includes POAG and age-related macular degeneration, should be avoided until treatment or surveillance strategies are proven useful in prospective randomized trials.  Additionally, it is important to use approved Clinical Laboratory Improvement Amendments (CLIA) labs and be cautious of direct-to-consumer testing services until FDA approved.

“Identifying someone who carries a gene-conferring susceptibility to glaucoma only indicates he or she is at increased risk, but does not predict if the person will actually get the disease,” said Dr. Chang, assistant professor, Byers Eye Institute, Stanford University, Stanford, CA. “This is different from single-gene disorders with high penetrance, where the likelihood of disease expression is very high.”


Genetic associations

Trabecular meshwork inducible glucocorticoid response (TIGR, a.k.a. myocilin) was the first gene associated with POAG and was identified by Polansky, et al. in 1997 through genetic-linkage analysis. However, myocilin, together with the two other original glaucoma genes identified by genetic linkage analysis-WDR36 and OPTN-only account for a small percentage of glaucoma.

LOXL1, discovered in 2007, was the first glaucoma gene identified using the new method of searching for unique, single-nucleotide polymorphisms (SNPs) in a genome-wide association (GWAS) study. In contrast to genetic linkage analysis, which is performed in large families who demonstrate disease inheritance in almost every generation, SNP analyses compare the frequency of many alleles in large populations of disease subjects versus unaffected controls to identify new genes associated with disease.

LOXL1 is a strong risk factor for PXF glaucoma, originally identified by Thorleifsson, et al. in a study involving Icelandic persons with glaucoma and normal controls. However PXF glaucoma is multifactorial, which is why some PXF syndrome patients do not go on to develop glaucoma.

Other studies


Subsequent studies have associated LOXL1 in different ethnic populations and even revealed that LOXL1 risk variants are also common in unaffected controls, rendering genetic testing less useful. In addition, the available evidence shows no association between LOXL1 and POAG, indicating that exfoliation is a secondary type of glaucoma, Dr. Chang said.

“Being a carrier of a high-risk LOXL1 allele does not mean a person will convert from PXF syndrome to PXF glaucoma,” Dr. Chang said. “These individuals may have a genetic predisposition, but it appears they also must be exposed to some environmental factor.”

Since 2010, GWAS studies have found multiple different genetic mutations related to common glaucoma risk factors, including increased vertical cup-to-disc ratio, optic disc area, high IOP, and low central cornea thickness, as well as genes involved in TGF-beta signaling and endothelial nitric oxide.  Many publications have come out from the collaboration of the NEI Glaucoma Human Genetics Collaboration (NEIGHBOR) led by Wiggs, et al. and Gene-Environment Interactions in Glaucoma (GLAUGEN) Research Consortium.

“Genetics research is helping us to understand a complex, multifactorial disease and to explain existing clinical signs with their associated molecular components,” said Dr. Chang. “This is important in terms of looking for potential future therapies.”

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