July 2013




Cataract editor's corner of the world

The current state and potential of AMD genetic testing

by Ellen Stodola EyeWorld Staff Writer


Bonnie An Henderson, MD

Angelina Jolie recently made headline news with her decision to undergo preventative mastectomies because of a strong family history and the revelation that she tested positive for a mutation of the BRCA1 gene. Genetic tests are becoming more common in all fields, including ophthalmology. Several companies now offer genetic testing for age-related macular degeneration. Although there are limitations to what information the genetic tests may offer, the ability to test for a genetic predisposition or to calculate the risks of developing wet AMD may offer some peace of mind to certain patients. EyeWorld interviewed Nancy Holekamp, MD, and Michael Gorin, MD, about advantages and disadvantages of AMD testing.

Bonnie An Henderson, MD, cataract editor


Genetic testing could offer a possibility for determining if a person is particularly at risk for developing age-related macular degeneration. These types of tests could be particularly valuable for those with a family history of AMD or those looking to undergo procedures where developing AMD would have a negative impact on results and future treatment. For example, cataract surgeons may want some indicator if a patient will develop AMD when considering a multifocal IOL or deciding what type of treatment a patient should pursue.

While there are advantages, there are also negatives to consider before immediately assuming that every patient should have genetic testing for AMD. Current tests for this have limitations on accuracy and effectiveness, and since it is not certain that everyone with a family history of AMD will automatically develop the disease, tests should mainly be reserved for those already showing some degree of AMD.

Nancy Holekamp, MD, director of retinal services, Pepose Vision Institute, Chesterfield, Mo., and professor of clinical ophthalmology, Washington University School of Medicine, Saint Louis; and Michael B. Gorin, MD, PhD, Harold and Pauline Price professor of ophthalmology, and chief of the retinal disorders and ophthalmic genetics division, Jules Stein Eye Institute, Los Angeles, weighed in on the topic, discussing two big tests right now, factors in determining how helpful the tests are, and potential disadvantages of AMD genetic testing.

AMD genetic tests available

Dr. Holekamp said there are currently two AMD genetic testing companies that have products commercially availablethe Macula Risk test (ArcticDx, Bonita Springs, Fla.) and the RetnaGene test (Sequenom Center for Molecular Medicine, San Diego). "Each test is looking at 12-15 variations in DNA that, along with smoking history and the degree of AMD already present in a patient's eye, can help predict the risk of progressing to advanced disease," Dr. Holekamp said. "The DNA variations each company chose to look at are slightly different with the exception that both look at DNA variations in complement factor H and ARMS2."

Dr. Holekamp said there is no specific indicator to determine how accurate these tests are, and instead of being FDA regulated, genetic tests are laboratory-developed tests (LDTs). "No licensing agency or regulatory agency mandates that the companies provide evidence of accuracy," she said. However, Dr. Holekamp noted that ArcticDx has published an algorithm of the first and second generation Macula Risk test, while Sequenom has performed a validation study for the first and second generation RetnaGene tests.

Though AMD genetic tests are a promising option, Dr. Holekamp said they should mainly be reserved for those who already manifest some degree of AMD on a dilated retinal exam. "We now know that genetics account for about 65% of the risk of developing AMD," she said. "However, we also realize that not everyone with a genetic predisposition goes on to have the disease."

According to Dr. Gorin, of the AMD genetic tests available, most provide selective testing of one or a subset of the genes related to AMD. "The tests fall into several groups," he said. There are those that look at targeted variants in one or more specific genes, those that do sequencing of specific genes, some that look at insertions and/or deletions in a selected gene, and a few that do a panel of variants. Dr. Gorin said there are multiple tests that are CLIA-approved, but there are only three that offer a risk estimate based on the test results. Of those three, only Macula Risk and RetnaGene use clinical data to determine the risk estimate. In terms of accuracy of these tests, Dr. Gorin said all of these tests employ methods that provide a high reliability for determining the sequence or variant for which they are testing. "However, if you are asking about the accuracy or reliability of the risk estimates derived from the genetic testing, then the answer is much less encouraging," he said.

Dr. Gorin noted that there are some problems and limitations with the Macula Risk and RetnaGene tests. "The RetnaGene test is very specific in what it is intended to be used for," he said. "It is designed to be used on people over the age of 64 who have AMD and for whom one is trying to calculate the risk of developing wet AMD." The RetnaGene test relies on a combination of genetics, clinical findings, and smoking exposure. However, it is not optimal for figuring out the risk of developing geographic atrophy from AMD or for predicting whether a younger patient will develop AMD. "At this time none of these tests are effective in that respect," Dr. Gorin said.

AMD genetic tests are being heavily promoted to the public, Dr. Gorin said, adding that the Macula Risk test is being promoted to optometric practitioners as well. "However, the benefits are limited," he said. "Though the Macula Risk website does provide guidelines for following up on people based on their degree of AMD risk, it doesn't add much to the care." Dr. Gorin stressed a similar point with the RetnaGene test, saying that there is limited benefit because the results of the test would not drastically shift management of AMD. "At this time, I feel that these tests are of limited benefit and, more often than not, can lead to misinterpretation and poor clinical guidance," he said.

Patients considering a multifocal IOL

eye factDr. Holekamp indicated that it could be valuable for cataract surgeons to make genetic testing available to patients who are contemplating a multifocal IOL. However, she said that the tests should only be used for those with a strong family history of AMD if the patient is already showing some evidence of AMD, like drusen.

Dr. Gorin has seen a number of patients who have had complications arise with their AMD by having a multifocal IOL, so the ability to assess the risk of developing this ahead of time could prove beneficial. If a patient has a family history, he or she could be more likely to develop AMD, but it is not guaranteed. "If you excluded those people with a positive AMD family history from having these lenses, you would block a disproportionate amount who would have benefitted from that lens," Dr. Gorin said. "If you use the argument of a negative AMD family history to justify the use of the lens, then you will be putting the lens in a lot of people who eventually develop AMD."

He said that relying on only genetic variants is not sufficient to identify the risk of AMD because there is not enough sensitivity and specificity to guarantee it. "At this time, the best recommendation would be to do a careful clinical assessment of the retina with diagnostics that can detect subtle drusen (especially reticular drusen) using high resolution spectral domain OCT, multispectral imaging and autofluorescence," he said.

Negatives of genetic testing

Though there are advantages of AMD genetic testing, there are negatives to consider as well.

"One potential negative would be providing false genetic counseling," Dr. Holekamp said. "That is why ensuring these LDTs are accurate and valid is so important." She said another possible negative would be performing the test without properly counseling and educating the patient. This could cause a misunderstanding of the results.

"Finally, a potential negative would be driving up the costs of healthcare, as each of these tests are reimbursed by Medicare and cost upward of $1,000 per test," Dr. Holekamp said.

Dr. Gorin also shared his concerns of genetic testing, one of which is some doctors may use it to try to coerce patients to alter their behavior or gain compliance by asserting that a certain person is at a high risk for the disease based on the results of the test. "Of course the flip side of this is that a low risk profile might make a person less likely to abide by good health practices," he said. "The current preventive therapies for AMD have relatively low risk and cost and thus genetic profiling has limited benefits. This may change dramatically if a therapy with substantial costs and/or risk for AMD prevention is developed and it becomes critical that we limit such therapies to those whose risk for disease warrant these treatment costs and risks." Dr. Gorin said the genetic tests are not highly predictive unless a patient has the highest or lowest risk profile, but the truth is that most individuals will fall within an intermediate range of risk, where the risk models are not sufficiently discriminating to predict a patient's future.

Editors' note: Dr. Holekamp has financial interests with ArcticDx and Sequenom CMM. Dr. Gorin has financial interests with Optherion (New Haven, Conn.) and Sequenom.

Contact information

Gorin: gorin@jsei.ucla.edu
Holekamp: nholekamp@gmail.com

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