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Gene associated with both juvenile, adult glaucoma
Investigators also found an OPTN gene mutation in normal- and high-tension glaucoma.
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SARASOTA, Fla. – Mutations in CYP1B1, a gene previously associated exclusively with congenital glaucoma, have now been implicated in adult-onset glaucoma, according to a study presented at the meeting of the American Glaucoma Society.
Nathan G. Congdon, MD, and colleagues also found that mutations in the optineurin (OPTN) gene are present in both normal-tension glaucoma (a previously documented finding) and high-tension forms of the disease.
Gene changes
Investigators sequenced the genes in 79 black, white and Asian families that included at least two members with primary open-angle glaucoma, as well as in 200 older individuals without the disease.
Among the glaucomatous families, which included one large black family with 41 members, they identified 176 potential sibships, which were ultimately narrowed to 52 confirmed sibships (37 white, three Asian and 12 black).
“Both among unaffected and affected people, it’s a relatively small proportion that have these [gene] changes,” Dr. Congdon told Ocular Surgery News, adding that the percentage of glaucoma patients with these mutations probably numbers in the single digits.
In their study, investigators found CYP1B1 mutations in 12% of affected families and OPTN mutations in four families. In comparison, the genes are seldom found among unaffected families.
“Because they’re exceedingly rare in the normal population, we do think that [these genetic mutations] are probably associated with disease; they’re actually disease-causing changes, and not just normal variance,” Dr. Congdon said.
Previous research
There are currently six known loci and three genes associated with glaucoma. One, the myocillin gene, is believed to account for 8% of glaucoma cases.
Dr. Congdon noted that the next step is to look for new loci where investigators might find genes associated with glaucoma. These genome-wide scans, and the development of hypotheses about where such mutations might be found, will be accomplished once more families are recruited into the study, he said.
In the meantime, as investigators search for new genes, they are also learning more about the ones they already know.
Sequencing the OPTN gene, for instance, confirmed a known base pair (bp) deletion in exon 5 and revealed 1 bp insertion in exon 4, according to the study. The findings also questioned the pathogenesis of OPTN allele M98K, which did not appear to be associated with glaucoma in the study group.
Role of race
Investigators did not identify specific genetic findings associated with race, perhaps because of a small sample size. Dr. Congdon noted that investigators are still recruiting more black families into the study.
“People of African descent are affected by glaucoma four or five times as frequently as people of European descent. And we also know that the coverage that they get – in terms of surgery, exposure to medicines and things – is probably somewhat less than it should be. ... from looking at blindness figures, it appears that people of African descent are going blind from glaucoma at rates that are significantly higher than white people,” he said. “So there’s a lot of interest obviously in better understanding this disease in people of African descent – and that’s something we really hope to focus on in our work.”
Future applications
In an interview, Dr. Congdon also discussed some of the long-term applications of genetic research.
“One can imagine certainly doing genetic screening and even genetic therapy, but I think those more invasive things are perhaps not going to be as practical as two other areas of import,” he said.
The future for genetic research is more likely to be in pharmacology and pharmacogenetics, which would allow more targeted therapies that go beyond the standard protocol of pressure reduction, he said.
“We’re able to determine by inexpensive and straightforward genetic tests whether someone is likely to respond to a typical class of medications or not, and I think that can help us tremendously in terms of knowing how to direct therapy,” Dr. Congdon said. “We spend a lot of money on medicines that maybe aren’t optimal for patients. I think optimizing the medical regimen would be a real advantage of pharmacogenetics.”
The second goal would be to achieve a better understanding of the pathogenesis of glaucoma to develop more rational pharmacological interventions, he noted.
“I think genetics at the end of the day, most importantly, will help us better understand this disease so we can treat it in ways that are perhaps more effective than what we have now,” Dr. Congdon said.
For Your Information:
- Nathan G. Congdon, MD, can be reached at the Dana Center, Wilmer Eye Institute, 600 N. Wolfe St., Rm. 120, Baltimore, MD 21287; 410-614-5561; fax: 410-502-8837; e-mail: ncongdon@jhmi.edu.