Spotlight ON TECHNOLOGY AND TECHNIQUE
The Genetic Connection
For the first time, it's possible to identify patients at risk for different types of glaucoma using a simple, in-office test.
BY CHRISTOPHER KENT, SENIOR ASSOCIATE EDITOR

It's probably fair to say that the "nature vs. nurture" debate has reached a truce. Both genes and environmental factors clearly play a part in shaping our bodies, our behavior and our health -- including our susceptibility to glaucoma. Indeed, researchers have already identified several genetic factors that indicate increased susceptibility to different forms of glaucoma.

This year, for the first time, a test for some of these genetic risk factors has become commercially available. Here's how it works, and what it may mean for your patients and practice.

Testing for aggressive glaucoma

OcuGene, developed by InSite Vision of Alameda, Calif., is a simple, in-office test that detects the presence of several glaucoma-related genetic variables. According to the company, the test detects them accurately more than 99% of the time.

The potentially most important part of the Ocugene test detects the presence of genetic marker MT-1 in the promoter region of the TIGR (trabecular meshwork inducible glucocorticoid response) gene. This marker is associated with a predisposition to a more aggressive form of glaucoma that some primary open-angle glaucoma (POAG) patients develop.

Studies have found that, on average, 15% to 20% of adult POAG patients test positive for this marker, and about 75% of patients with this marker develop the more aggressive form of glaucoma. Patients with this type of glaucoma often suffer greater visual field deterioration and/or optic nerve damage than patients with less aggressive forms of glaucoma. According to InSite Vision, patients who should be tested for this marker include those diagnosed with POAG, those showing signs of disc cupping and/or visual field changes, patients with high IOP despite treatment, and those with a family history of glaucoma.

If the test result is positive, you may want to treat the patient more aggressively and monitor the patient more frequently. If the test result is negative, the odds that the patient will develop the more severe form of glaucoma are significantly lower -- about the same as the odds of any POAG patient who shares similar nongenetic risk factors.

Testing for greater vulnerability

The current OcuGene test also detects the presence of several mutations in the coding region of the TIGR gene. This part of the test may be useful in fewer cases because it only detects three out of more than 40 possible mutations in the gene's coding region, and these mutations only occur in a limited number of glaucoma patients. However, these mutations are known to have relevance to adult POAG, and clinical data regarding these mutations is substantial; the presence of these mutations indicates a 90% to 100% probability of developing glaucoma, particularly after age 40. (See the graph on page 132.) Of course, an environmental trigger and/or modifier genes may be involved, so there's no absolute guarantee that a specific patient will develop glaucoma at a given age.

In addition to testing glaucoma suspects, InSite Vision recommends that other genetically related family members also be tested for these markers if a current glaucoma patient tests positive. Because of the genetic link, as many as 30% of blood relatives could also have the mutation, indicating a strong likelihood that glaucoma will develop at a later time. (Note: This is probably not the right test for families with a history of early onset juvenile glaucoma.)

At the very least, a family member's positive result signifies the need for more frequent exams and monitoring. A negative result simply means that the patient's risk of developing glaucoma is about the same as the risk faced by most other people with similar nongenetic risk factors.

Performing the test

To determine whether a patient has any of these genetic risk factors, you use two provided cotton swabs to obtain DNA samples by rubbing the swabs gently against the inside of the patient's cheek or the patient's gums; then you ship the samples to Quest Diagnostics (a CLIA-certified lab) for analysis. Test results are returned in about 2 weeks. The OcuGene test kit contains all the materials, instructions and shipping forms you need.

The test is not yet reimbursable, so the patient must pay for it. The current cost of the test is about $200 (comparatively inexpensive for a genetic test). Test results are confidential.

Feedback from the field

Spero Kinnas, M.D., F.A.C.S., who practices at the Westchester Eye and Laser Center in Westchester, Ill., has used the OcuGene test several times when glaucoma seemed an obvious possibility. "This is a worthwhile test, particularly if you have risk factors or a diagnostic dilemma," he says. "Basically, you have to weigh the cost of the test against the odds of getting a positive. Only one out of four may be positive, but if the test is positive, it means you've hit a home run."

In one case encountered by Dr. Kinnas, the mother and siblings of a patient all had enlarged discs. The mother also had elevated IOP. When Dr. Kinnas tested the original patient and mother, both had the MT-1 marker. "This is strong evidence that glaucoma runs in this family," he notes.

Murray Fingeret, O.D., who practices in Hewlett, N.Y., has tested about 35 patients since April. (Because he's been providing feedback to InSite Vision, his initial patients weren't required to pay for the testing, so cost was not an issue.) "This version of the test is meant to be used as a management tool," he says. "I think of it as a crystal ball; it tells you whether a patient may develop the worse form of glaucoma.

"I've used the test on people with monocular or asymmetric glaucoma, glaucoma suspects and patients with high IOP -- anyone I was concerned might progress. I make sure they know the test is new and limited in scope, but that it may provide useful information about their prognosis.

"Out of those tested, I only had two positives. Neverthe-less, this could be important information for those two pa-tients, and I was able to tell the others that they don't have the genetic marker for the more aggressive form of glaucoma. The patients have all been happy to have this information."

Dr. Fingeret is well aware of the test's current limitations. "So far we've seen limited data supporting the test's clinical usefulness. However, more data by other researchers should be published soon. Until then, the test's limitations need to be explained to patients.

"Genetics should eventually become a powerful tool in the management of glaucoma," he adds. "This is just the commercial beginning."

Taking the first step

Other genetic markers are already known to be connected to the development of normal-tension glaucoma and primary congenital glaucoma; InSite Vision hopes to have tests for them available by next year. In the meantime, OcuGene is a promising start.

Visit www.ocugene.com or call 1-866-OcuGene (628-4363) to order test kits or get more information about OcuGene.

Are you aware of new products or technology that have made (or are likely to make) a significant difference in practice? Contact Christopher Kent at kentcx@boucher1.com  to find out about possible coverage in a future issue.