Glaucoma is key area of genetic research

Editor's Note: Research into the genetics of ocular disease is paying off with discoveries of new genes associated with both common and rare eye conditions. Gene therapy, however, could be 5 to 10 years away for many eye diseases. In this second article of a two-part series, gains in knowledge of glaucoma, myopia, and retinitis pigmentosa are covered as well as a promising therapy for age-related macular degeneration (AMD)-RNA interference. The first article in the series (Ophthalmology Times, Nov. 1, 2005) discussed the progress in the areas of AMD, Leber's congenital amaurosis, and familial exudative vitreoretinopathy (FEVR).

Glaucoma presents a significant challenge for researchers seeking to adapt what is learned about genetics in labs to strategies that can be used in patient care.

"It will be a while before genetic information in glaucoma can be applied in terms of treatment," said Julia E. Richards, PhD, associate professor of epidemiology, School of Public Health, and associate professor of ophthalmology and visual sciences, Medical School, University of Michigan, Ann Arbor.

Researchers are still in the early stages of trying to identify the key biochemical pathways and structures that should be targeted with treatments, she added.

"More genes [associated with glaucoma] need to be found in order to piece together the picture of the biochemistry and cell biology before treatments can be developed," she said. Most cases of glaucoma have not yet been accounted for according to the genes discovered so far, Dr. Richards added.

The first gene that was discovered accounts for about 3% of cases of POAG.

"It's unclear what percentage is attributable to the second gene, due to different statistics in various studies, and little is known about what fraction of disease might be traced to the third gene," she said.

"None of these are big players, and there's still a lot to be discovered. The result is that we have a jigsaw puzzle we are putting together as far as the biochemistry and cell biology that would inform the development of treatments, but we still have huge regions missing from the picture," Dr. Richards added.

"Enough breakthroughs have been made at this point to show us that it's all feasible and that we can find these genes," she said.

Difficulty with genes

The search for genes implicated in glaucoma is complicated by the fact that the disease is complex and heterogeneous and has a late onset. Even in very large families, there may be only a few affected individuals alive at any one time, Dr. Richards explained, and this technically limits the scope of what researchers can do with genetics. Researchers are often forced to pool information from different families to try to get statistically significant results, yet what is happening in different families may be unrelated.

"Even if you were to take one diagnosis, primary open-angle glaucoma, it is not one disease. It is a group of diseases that has a similar set of clinical presentations but that may have different underlying causes," she said. And in addition to the multiple genes that could be involved in glaucoma, many nongenetic factors can also contribute to development of disease, influencing such aspects as how early the disease occurs and its severity.

Researchers pursuing the genetic aspects of glaucoma clearly face a daunting task, and in response their strategies include maintaining a lookout for large individual families that might be big enough to stand alone in a study and achieve statistical significance, conducting sibling pair studies, and performing ordered subset analysis.

Glaucoma researchers also follow up clues pertaining to ancestry or ethnic background. Researchers at Oregon Health and Science University, Portland, identified a glaucoma locus and determined that some of the family members had Greek ancestry, so they took their study to Greece where they found several families who had glaucoma that seemed to be associated with the same region of the genome.