Nature, not Nurture
On the trail of genes associated with glaucoma.
BY GLARA YI, O.D., CHRISTOPHER J. QUINN, O.D., F.A.A.O.

Since the human genome project began, we've speculated that one day we may be able to run a blood test and diagnose glaucoma or perhaps use gene therapy to treat it. Although we haven't arrived at that point yet, promising discoveries have been made, as we'll describe here.

The Myocilin gene

Many genes are now known to be associated with glaucoma and aqueous production, but much of the research has been centered on the TIGR (trabecular meshwork-induced glucocorticoid response) gene.

The TIGR gene was first discovered to be associated with long-term dexamethasone treatment in human trabecular meshwork cells. Since then, it has been renamed the myocilin (TIGR/MYOC) gene.

The TIGR/MYOC gene is thought to be involved in regulating intraocular pressure (IOP), although its exact function is unknown. Mutations here have been identified most often in juvenile-onset open-angle glaucoma patients. Eight percent to 20% of these patients have such mutations, yet only 3% to 5% of adult-onset primary open-angle glaucoma patients (POAG) did.

The relationship of the gene to juvenile-onset open angle glaucoma is tighter because of the autosomal-dominant inheritance pattern. Although the relationship of the TIGR/MYOC gene to POAG is a little disappointing, it's an important starting point in the search for the pathophysiology of glaucoma.

Most recently, Rezaie and associates identified the Optineurin (OPTN) gene that may be implicated in POAG. Optineurin appears to play a protective role against the development of glaucoma. Researchers speculate that the OPTN gene may inhibit tumor necrosis factor-alpha (TNF-alpha), which has been shown to cause apoptosis or programmed cell death in the retinal nerve fiber layer. Any mutation in the OPTN gene facilitates cell death. Mutations were found in 16.7% of POAG patients, including those with normal tension glaucoma. Nevertheless, we need further studies.

A complex puzzle

It's interesting that two different genes have been implicated in glaucoma. The TIGR/MYOC gene is closely related to increased IOP; a defective gene results in increased IOP. The OPTN gene appears to protect against glaucoma; a mutation here results in increased cell death not necessarily related to IOP. The genetics of glaucoma are intricate and diverse. A mutation anywhere along the pathway could lead to nerve fiber layer damage and ultimately loss in visual field.

Dr. Quinn is center director of Omni Eye Services, a regional optometric co-management center with offices in New Jersey. He's president of the New Jersey Society of Optometric Physicians.

Dr. Yi is center director of Omni Eye Surgery of New York, an optometric co-management center in New York City. She's a frequent lecturer on topics related to ocular disease and co-management.

References available upon request.