Did you ever wonder about … genetic testing for glaucoma?

Genetic testing may soon help to assess a patient’s risk for, and predict treatment effectiveness of, certain types of primary open-angle glaucoma.

Issue: March 15, 2006

ByDouglas J. Rhee, MD

Genetic testing holds the promise to help assess the risk of an individual developing glaucoma, predict the severity of disease phenotype and even predict the effectiveness of treatment.

In 2001, InSite Vision Inc. released OcuGene, the first commercially available genetic test for glaucoma. Initially, it tested for the presence of four mutations of the myocilin gene and featured the mt-1 single nucleotide polymorphism. (See the glossary on this page for this and other terms used in this article.) The currently available OcuGene kit tests solely for the mt-1 polymorphism, whose prognostic value for predicting an aggressive phenotype of primary open-angle glaucoma (POAG) is controversial.

So why aren’t we doing genetic testing on all our POAG and POAG-suspect patients?

Environment and genes

In part, this is because the known gene mutations are responsible for a minority of POAG.

Douglas J. Rhee, MD [photo]
Douglas J. Rhee

What we describe as open-angle glaucoma – characteristic changes in the optic nerve head, typical optic nerve localizing visual field changes, an elevated IOP with open angles and the lack of secondary causes – is a constellation of findings that probably represents numerous distinct defects that result in a final common pathophysiology that abates to some degree from the lowering of IOP. Glaucomas are likely the result of a combination of environmental influences and genetic predisposition.

To date, the studies of numerous families with high rates of glaucoma have revealed 11 unique loci associated with the POAG phenotype (these loci are named GLC1A through K). In these families, the POAG phenotype is inherited in a simple Mendelian fashion (ie, autosomal dominant or recessive) indicating a single causative gene. There is variable penetrance of the phenotype, which indicates that there are likely environmental components or effects of modifying genes that contribute to the ultimate development of POAG. Within these 11 loci, three genes have been identified: TIGR/myocilin (GLC1A), optineurin (GLC1E) and WDR36 (GLC1G).

The best-studied gene is myocilin. Myocilin is expressed in normal people and is upregulated by corticosteroids, TGF-beta and mechanical stretch of trabecular meshwork cells. There are more than 40 reported mutations in the myocilin gene that are associated with a high-pressure, open-angle glaucoma phenotype. Myocilin mutations account for approximately 3% to 5% of POAG. If you are seeing more than 20 POAG patients in a week, you are probably seeing someone with myocilin-associated glaucoma every week.

However, it is estimated that the amount of POAG that can be attributed to mutations in all three genes combined is less than 10%.

Testing and treatment

What about the rest of our POAG patients? Most of them are likely polygenic (ie, there are mutations or “hits” in at least two distinct genes that result in the glaucoma phenotype). One defect is likely in the trabecular meshwork or uveoscleral track that affects aqueous drainage, while another mutation could affect the susceptibility of the optic nerve to barotrauma. The posterior segment defect could be in the ganglion cells, Mueller cells or astrocytes, affecting proteins that regulate blood flow, connective tissue elasticity, etc.

But is genetic testing of glaucoma patients useful?

“Yes, for certain types of POAG,” Janey L. Wiggs, MD, PhD, said. “For people with onset of POAG before age 40 there may be a myocilin mutation, and people with very severe low-tension glaucoma may have the E50K mutation in the optineurin gene.”

Knowing the genotype can help us give some realistic prognostic information for the specific mutation where the genotype and resulting phenotype is known. “Knowing who has the mutation can also help focus our surveillance of a patient,” Dr. Wiggs said.

Knowing the genotype can also help guide our management decisions. “Many patients with myocilin mutations, particularly those mutations that cause juvenile onset open-angle glaucoma, do better with surgery,” Wallace L. M. Alward, MD, said.

Glossary

A single nucleotide polymorphism (SNP) refers to a single base change in the DNA sequence of a gene that occurs in an appreciable frequency in the population. Some authors indicate that the frequency should be greater than 1% of the population, while others do not include this exact figure as part of the definition. These changes either have no effect or can lead to functional differences in the final protein product. If the DNA change results in an abnormal protein product, then the change is a mutation.

A locus (singular; loci is plural) refers to a physical location or area of a chromosome. Within a locus, numerous genes can be found ranging from a handful to more than 100, depending on the size of the area specified. The nomenclature of glaucoma loci is as follows: “GLC” refers to “glaucoma;” the number “1” refers to an open-angle glaucoma phenotype; the following letters A through G represent the chronologic order in which the loci were discovered.

Penetrance refers to the rate that a person with the mutation in question will have the disease. For example, myocilin mutations have approximately a 90% penetrance rate. Thus, a person with a mutation in the myocilin gene has a 90% chance that they will develop glaucoma.

Source: Rhee DJ

Timeline for testing

How soon we will routinely use genetic testing for glaucoma remains to be seen. Dr. Wiggs believes it will be a gradual process, but she predicts that we will be routinely doing genetic testing for glaucoma within a decade.

“We are getting closer to identifying genes that may be present in a significant number of people with POAG,” R. Rand Allingham, MD, said. In a collaborative study with Dr. Wiggs, Dr. Allingham recently reported a new locus (GLC1I) that was present in 17% to 20% of their sample of 86 families.

“In a follow-up study, my colleagues and I have also detected the GLC1I locus in our POAG dataset,” Julia E. Richards, PhD, said. The causative gene within that locus has not yet been elucidated.

Although some laboratories have the capabilities to test for mutations in glaucoma genes, genetic testing for glaucoma is not used in a large-scale clinical setting. However, keep checking in; this is likely to change in the near future.

For Your Information:

Douglas J. Rhee, MD, is an assistant professor of ophthalmology at Harvard Medical School and on the faculty of the Massachusetts Eye and Ear Infirmary. He can be reached at 243 Charles St., Boston, MA, 02144; 617-573-3670; fax: 617-573-3707; e-mail: dougrhee@aol.com. Dr. Rhee has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Janey L. Wiggs, MD, PhD, associate professor of ophthalmology at the Massachusetts Eye & Ear Infirmary, Harvard Medical School, can be reached at 617-573-6440; fax: 617-573-6439; e-mail: janey_wiggs@meei.harvard.edu.

Wallace L.M. Alward, MD, professor and vice chair of ophthalmology and director, glaucoma service at the University of Iowa, can be reached at 200 Hawkins, Iowa City, IA 52242; 319-356-3938; fax: 319-353-7699.

R. Rand Allingham, MD, professor of ophthalmology and chief of the glaucoma service at Duke University, can be reached at Duke University Eye Center/aeri-3rd Floor, Erwin Road, Box 3802, Durham, NC 27710; fax 919-681-8267; e-mail: rand.allingham@duke.edu.

Julia E. Richards, PhD, associate professor, department of ophthalmology and visual sciences, department of epidemiology at the University of Michigan, can be reached at 1000 Wall St., Ann Arbor, MI 48105; 734-936-8966; e-mail richj@umich.edu.

InSite Vision Inc., maker of OcuGene, can be reached at 965 Atlantic Ave., Alameda, CA 94501; Web site: www.insitevision.com.