Gene variant linked to glaucoma progression

Testing for presence of the mt.1(+) gene variant may be warranted in patients with a family history of juvenile glaucoma, study suggests.

Issue: April 1, 2004

The rate of progression of glaucoma may be influenced by the presence of a variant in the myocilin gene, according to a clinical study. The mt.1(+) variant in the gene was found to be associated with faster glaucoma progression, said Jon R. Polansky, MD, one of the study’s authors.

“We found a clear and statistically strong association of the genotype with glaucoma progression, independent of other baseline risk measures such as IOP and visual field,” said Dr. Polansky, at the First Annual Ocular Surgery News Symposium — Glaucoma: Improving Your Odds, in Las Vegas.

Using the Cox proportional hazard model of statistical analysis, “we found that the greatest risk factor for progression was having this variant, this mt.1(+) variant, and it was significant at the .004 level,” said Dr. Polansky, of the University of California, San Francisco.

About 15% of people have the mt.1(+) variant, according to previous studies, he said.

The practical aspect of their finding, Dr. Polansky said, is that patients who may be at risk of glaucoma due to family history or other risk factors, may elect to have a test done for the mt.1(+) variant. With the OcuGene test from InSite Vision, “the patient can define for him- or herself whether they are in this high risk category, and the ophthalmologist can use this private information to then decide how aggressive they should be, how much extra care they might require,” he said

A positive result on the test might also improve patient compliance with medication regimens, he suggested.

Earlier research

The myocilin gene is sometimes referred to as the TIGR gene, for trabecular inducible glucocorticoid response. The abbreviation TIGR/MYOC is also often used for the gene.

Dr. Polansky noted that earlier studies have linked the myocilin gene to juvenile glaucoma. About 2% to 4% of glaucoma is known to be due to defects in the gene, he said.

“The gene itself was jointly discovered through separate research efforts that we were doing at UCSF for many years, on steroid glaucoma, or what has been called oxidative stress to the cells,” Dr. Polansky said.

“We became interested in toxic effects on the trabecular cell, or oxidative injury, as a mechanism by which we could explain what was being seen in the laboratory, which was a gradient of damage in the trabecular meshwork, which was greater closer to the anterior chamber than as you move toward Schlemm’s canal,” he said.

This hypothesis links with other researchers’ work indicating that oxidative stress may also be responsible for tissue changes in cataract and macular degeneration, Dr. Polansky said.

“That’s how we came across this gene,” he said. “we were looking for what might be unusual in the trabecular meshwork … that might explain why that particular cell would make an unknown product, that would be induced by either glucocorticoids or the oxidative injury.”

“I felt if we could come up with a unique product that was produced by both, we might have a gene that was involved in the cause of the disease, and we cloned (the myocilin) gene.”

Dr. Polansky said he has a commercial interest in the gene because it was patented through UCSF as a cause of primary open-angle glaucoma and steroid glaucoma.

Clinical study

Dr. Polansky described a clinical study in which he collaborated with George L. Spaeth, MD, and statistician R.P. Juster to gauge the gene’s effect in patients. The study was published last year in the journal Clinical Genetics.

Their analyses were based on 147 patients with open-angle glaucoma over age 35 with an average follow-up of about 15 years.

Dr. Spaeth assessed patients’ disease progression based on an eight-point system, which uses measurements of both visual field and optic disc changes. In patients that had been followed for 20 years, Dr. Polansky said, more progression could be seen in the patients with the mt.1(+) variant.

“You could see a separation beginning 6 to 10 years out in which you saw more progression of the mt.1(+) individuals as a group,” he said.

The data was subsequently analyzed using Cox proportional hazard model analysis, Dr. Polansky said, similar to what was used in the Ocular Hypertension Treatment Study.

“This is necessary because the subjects are at risk for further disc and field changes, so you have to do this type of analysis,” he said.

The study found that the mt.1(+) variant had independent effects on disease progression, taking into account other relevant disease-related baseline risk factors, including age, family history, initial drug treatment, diabetes, gender, myopia and initial disease severity, according to the published paper.

For Your Information:

Jon R. Polansky, MD, can be reached at the department of ophthalmology, University of California-San Francisco, San Francisco, CA 9413; phone/fax: 415-388-0389; e-mail: rpj@169.ucsf.edu.

Reference:

Polansky JR, Juster RP, Spaeth GL. Association of the myocilin mt.1 promoter variant with the worsening of glaucomatous disease over time. Clinical Genetics. 2003:64:18-27.