Debate Over the Value of Genetic Markers for AMD Continues

By Rachel M. Renshaw, Editor-in-Chief
 

Recently published analysis of DNA and data from AREDS demonstrates a role for genotype-directed nutritional therapy in patients with moderate agerelated macular degeneration (AMD), said Carl Awh, MD, in his presentation at the American Academy of Ophthalmology (AAO) Annual Meeting in New Orleans.1 However, in the same session, immediately following Dr. Awh’s presentation, Emily Chew, MD, said that an alternative statistical analysis performed by the National Eye Institute failed to find sufficient evidence to support genetic testing for this indication. Dr. Chew also recommended that the AAO maintain its position, established last year, against routine genetic testing for AMD and other complex eye diseases. That recommendation, from the AAO Genetic Testing Task Force led by Edwin Stone, MD, has guided the Centers for Medicare and Medicaid Services to not reimburse physicians for these tests.

The Argument for Individualized Supplementation

Dr. Awh presented data from a study of 2 genetic polymorphisms, complement factor H (CFH) and age-related maculopathy sensitivity 2 (ARMS2), published in a recent issue of Ophthalmology.2 The study, further analyzing data from AREDS, demonstrated that supplementation with antioxidants and zinc can lower the risk of progression of moderate AMD in certain individuals. This subanalysis looked at the response of individuals with 1 or 2 CFH or ARMS2 risk alleles to components of the AREDS formula.

Dr. Awh said that an analysis of approximately 1000 patients followed for up to 12 years in the AREDS showed that subjects who have 1 or 2 CFH risk alleles were more likely to benefit from the use of antioxidant supplements alone, rather than the full AREDS supplement. In these patients, treatment with zinc, either alone or as a component of the AREDS formulation, was associated with increased AMD progression compared to treatment with antioxidants alone. The data also showed that individuals with ARMS2 risk alleles were more likely to benefit from zinc supplementation alone, while they were at a higher risk of disease progression when treated with antioxidants. For those who were homozygous for both CFH and ARMS2 risk alleles, the zinc and antioxidants in the AREDS formulation had no significant treatment benefit.

“If we look at our projected progression rates and the relative frequency of these genotype groups in the AREDS population, we predict that the optimal treatment for 49% of study patients is something other than the AREDS formulation,” Dr. Awh said.

If all of the individuals studied in the trial were treated with genotype-directed therapy, Dr. Awh said, the reduction in 10-year progression to advanced AMD could potentially be 33% with genotype-directed supplementation vs 14% with the AREDS formulation.

NEI: More Data Required to Validate

Dr. Chew stated at the AAO session that the analysis by Awh et al was not sufficiently powered to show statistical significance. She referenced a previous study by Klein et al,3 which evaluated the genetic interactions between CFH and LOC3877/ARMS2. In this retrospective analysis, the authors found no significant differences in response between 6 genotype groups assigned to antioxidants plus zinc, placebo, antioxidants alone, and zinc alone. The conclusion of this study was that the results did not justify routine genetic screening.

Recently, the AREDS Research Group evaluated 2 AREDS populations: participants from AREDS with category 3 AMD, which was similar to the population studied by Awh et al, and a population of category 3 and 4 AMD patients for whom AREDS supplementation would be recommended.4 These populations were were tested for interaction with genotypic associations with the 4 treatment groups. The researchers did not find any statistically significant differences in genetic interaction with the 4 treatment groups.

In regard to the data from Awh et al, Dr. Chew said, “Subgroup analyses are retrospective in nature and markedly underpowered in the situation. One cannot make treatment recommendations based upon such analyses.”

Further Comments

In an interview with Retina Today, Dr. Awh said, “As Dr. Chew demonstrated, the subgroup analysis performed by the NEI is insufficiently powered to come to a meaningful conclusion. However, they did not replicate our analysis, which was peer-reviewed and published in Ophthalmology, nor have they have demonstrated any flaws in our statistics. We acknowledge the retrospective nature of our subgroup analysis. However, we used all available DNA collected by AREDS for the purpose of analyses like this one. Our analysis was of data from almost 1000 patients followed meticulously for over a decade by the NEI. Furthermore, the AREDS recommendations were themselves based on a subgroup analysis— there is nothing inherently incorrect about conclusions derived in this manner.”

“The main point is that the NEI really hasn’t proved us wrong,” Dr. Awh continued. “They have simply failed to validate our findings though a completely different statistical analysis from ours. We believe that we have provided enough evidence that show this to be, at the very least, worthy of further investigation.”

Dr. Chew told Retina Today in an interview that she also believes more study is warranted. “We will continue to work with the AREDS data, which is available for others to use as well. We are not finished by any means,” she said. “We do not have adequate data showing that you can use antioxidants only or zinc only for reducing the risk of AMD, and so this is why we recommend that the AAO does not change its stance on genetic testing.”

Future Directions

Dr. Awh told Retina Today that he believes personalized medicine and genetics represent the direction of the future, and he continues to question the AAO’s recommendation against genetic testing.

“The commercially available physician-ordered tests for AMD risk differ fundamentally from direct-toconsumer tests. The current generation of AMD genetic tests meet all the criteria defined by the AAO Genetics Task Force. Our recent publication adds to the substantial body of peer-reviewed literature demonstrating the value of genetic testing for patients with AMD.” Why shouldn’t thoughtful clinicians have access to these tests?” he continued. “It is unreasonable to state that testing should be confined to research settings. I use the example of optical coherence tomography (OCT). The images from first-generation OCT were crude, and we understood relatively little about them. Had we restricted OCT to research laboratories and kept the technology out of the hands of practicing physicians, we never would have learned as much as we have in the last 5 or 10 years. At some point, new technologies must be put into the hands of thoughtful clinicians. Genetic testing for AMD has reached this point.”

One of the points that Dr. Chew made during her presentation was that the costs to the health care system would be great should genetic testing for AMD be recommended by the AAO and covered by CMS.

“Millions of people would be affected, and the cost would be huge if genetic testing is necessary,” Dr. Chew said. “We must be certain [about the value of testing].”

However, Dr. Awh said that the cost of a genetic test for AMD, based upon current Medicare guidelines, would be around $300 for a test that would be administered only once in an individual’s life. “The cost is pretty modest, and the potential savings to society, in terms of both financial and quality of life benefits, is huge,” he said. “Our results suggest that we could double the reduction in AMD progression if [we] gave everyone their optimized nutritional supplement based on genetic risk factors. This could result in several hundred thousand fewer cases of advanced AMD over a 5-year period.”

According to both presenters, the AAO Genetics Task Force will meet in the near future to go over the published and presented data and determine whether changes will be made to the AAO’s recommendation.

Carl C. Awh, MD, practices at Tennessee Retina in Nashville. Dr. Awh reports the following financial interests: Arctic Dx advisory board member, consultant, and shareholder. He may be reached at carlawh@gmail.com.

Emily Y. Chew, MD, is the study chair of the AREDS 2 study. She is a member of the Division of Epidemiology and Clinical Research at the National Eye Institute. Dr. Chew reports no relevant financial interests. She may be reached at echew@nei.nih.gov.

  1. Awh CC. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age related macular degeneration. Paper presented at: the American Academy of Ophthalmology Retina Subspecialty Day. November 18, 2013; New Orleans.
  2. Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120(11):2317-2323.
  3. Klein ML, Francis PJ, Rosner B, et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology. 2008;115(6):1019-1025.
  4. Chew E; AREDS Research Group. Interaction of genetic risks and AREDS supplements in progression to late AMD in the Age-Related Eye Disease Study (AREDS). Paper presented at: the American Academy of Ophthalmology Retina Subspecialty Day. November 18, 2013; New Orleans.
 

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Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.