Lara C. Pullen, PhD

November 15, 2012

CHICAGO, Illinois — The American Academy of Ophthalmology (AAO) has reiterated its position that eye physicians and surgeons should avoid genetic testing for late-onset primary open-angle glaucoma and age-related macular degeneration (AMD). As of now, the standard clinical examination is more sensitive and specific for detecting treatable disease than any genetic test.

Edwin M. Stone, MD, PhD, director of the University of Iowa Institute for Vision Research in Iowa City, presented the AAO's position here at a press conference held during the AAO 2012 Annual Meeting. Dr. Stone began his presentation by acknowledging that AMD is one of the most significant medical conditions facing the world today, and that prevention is key to relieving this health burden.

"I think that the Achilles' heel of age-related macular degeneration is that genes play a very important role," he explained. He believes that research in genetics will elucidate molecular mechanisms, create in vitro and animal models, and enable novel mechanism-specific treatments.

Two genes in particular have been significantly associated with the development of AMD: ARMS2 and complement factor H (CFH).

Despite this, the AAO's Task Force on Genetic Screening has recommended against genetic testing. This stems from the fact that current AMD genetic tests have not been shown to improve clinical outcome. Currently, the tests are less sensitive and specific than clinicians themselves. There are also no mechanism-specific therapies available to treat a patient identified as being at genetic risk for AMD.

Dr. Stone briefly reviewed data from the Pepose Institute, Illinois Retina (PIIR) study. In PIIR, 103 subjects were tested by 2 commercial labs: Arctic Dx (Macula Risk) and Sequenom (RetnaGene). The analysis involved 97 subjects who had sufficient genotypic and clinical information for comparison (17 normal controls, 33 with dry AMD, and 47 with choroidal neovascularization).

Genotyping Errors

Although there were no detectable genotyping errors in the data generated by Sequenom, there was a major error in the Arctic Dx data. Arctic Dx failed to detect the CFH H3 haplotype in any of the patients. This is a significant error because that haplotype is present in about 30% of the population.

PIIR patients were assigned a risk rank, from 1 (mildest) to 97 (most severe), on the basis of the risk score assigned to them by each company. The risk ranks were compared with each other and with the clinical phenotype assigned by investigators.

The investigators found only a moderate correlation between the 2 tests. Even more worrisome was Dr. Stone's statement that the tests were "so uncalibrated with reality that one can't even measure it."

Dr. Stone concluded by stating that physicians and patients should avoid routine genetic testing for AMD until treatments have been shown in clinical trials to be of benefit to individuals with specific disease-associated genotypes.

Paul Mitchell, MD, professor of ophthalmology at the University of Sydney in Australia, was quick to agree. "I fully support this recommendation," he said.

However, he added that the research to date on genetic risk factors for AMD is intriguing, and explained that "dietary advice does link to some extent with the genes.... People who ate fish on a regular basis, even if they were gene carriers, lowered their risk to nongene carrier levels."

Dr. Stone and Dr. Mitchell have disclosed no relevant financial relationships.

American Academy of Ophthalmology (AAO) 2012 Annual Meeting. Presented November 12, 2012.