Researchers studying the molecular genetics of glaucoma are discovering new genes by applying high-powered technologies to their analysis of family pedigrees and looking for clues in animal models. These genetic discoveries are moving this field toward clinical applications.
Dr. Alward reviewed many of the advances in the study of the molecular genetics of glaucoma that have occurred in the past few decades and looked ahead to future developments as he presented the Robert N. Shaffer Lecture at the annual meeting of the American Academy of Ophthalmology this past November.
Although he and the late Dr. Shaffer shared an interest in gonioscopy, they also had a mutual passion for the genetics of glaucoma.
In the decades since Dr. Shaffer's paper appeared, researchers have identified 14 linked sites for primary open-angle glaucoma (POAG): GLC1A to GLC1N. This means that 14 areas exist in the DNA where a gene might be located, although the gene itself may not be known.
Three genes have been described at those loci. The myocilin gene is involved in many cases of juvenile-onset glaucoma but, more importantly, causes 3% to 5% of cases of POAG in adults.
A second gene, optineurin, causes autosomal dominant normal-tension glaucoma, which is a rare disease. Optineurin, however, is important because it may be involved in the process that damages the optic nerve, according to Dr. Alward.
The role of the third gene, WDR36, in POAG is controversial and unclear, but it remains the subject of intense study, he said.
Although the discovery of these genes is significant, the clinical impact is limited.
"In total, we know the genetic origin of less than 5% of POAG," Dr. Alward said.
In addition, very little has been discovered about the genetics of angle-closure glaucoma. Investigators have found two linkages for dominant nanophthalmos and one gene for autosomal recessive nanophthalmos, which is quite rare, he said. Two known linkages for primary congenital glaucoma exist in addition to an important gene, CYP1B1.
Secondary, syndromic glaucomas
Research gains also have been made in the understanding of secondary and syndromic forms of glaucoma.
"The most exciting [and] relatively new finding in secondary glaucomas came out in 2007, and that's the LOXL1 gene," Dr. Alward said. Scientists from a biopharmaceutical firm (deCODE genetics) and colleagues in Iceland and Sweden observed that two single nucleotide polymorphisms (SNPs) on the LOXL1 gene were associated strongly with exfoliation syndrome and exfoliation glaucoma. The protein encoded by the LOXL1 gene is involved in the production of elastin fibers.
More than 300,000 SNPs from patients with glaucoma and controls were analyzed using high-resolution SNP chips and additional SNPs from public databases.
This finding is significant because of the exceptionally strong association with exfoliation syndrome, he said.
An individual in the highest-risk genotype would be 700 more times likely to develop the exfoliation syndrome than someone in the lowest-risk genotype, according to Dr. Alward. The findings have been replicated around the world, and one of the SNPs appears to be the disease-associated variation.
"It's very important for clinicians to be aware that most people who have this sequence variation do not get exfoliation syndrome. You should not run out and test all of your patients for LOXL1," he said. "If you look at the original data, there were 75 people with this sequence variation who did not have exfoliation for every one who did have exfoliation. Yet, it's a tremendously important finding and it's a substrate upon which people develop this disease, although there's a lot more for us to figure out."
Other advances in secondary or syndromic glaucomas include the discovery of the PAX6 gene, which is associated with aniridia, and two genes, FOXC1 and PITX2, associated with Axenfeld-Rieger syndrome. Nail-patella syndrome, which is associated with POAG, has been shown to be caused by mutations in the LMX1B gene.
Researchers also have learned more about the genetics of Peter's anomaly.
"It's an interesting 'garbage basket' disease in that all of the genes that can cause developmental glaucomas in isolated case reports have been shown to cause Peter's anomaly," Dr. Alward said.