Eyeworld

– 9:24 AM Page 1 EW NEWS & OPINION 22 Genetic tests to evaluate known markers are now available for age-related macular degeneration A ge-related macular degen- eration (AMD) affects about one in three people over the age of 75; by 2025, 44% of the U.S. population will fall into this age range. In AMD, genetic factors ac- count for 60% to 70% of the causes, compared to 10% or less in other complex diseases. Yet the advantages and disadvantages of including ge- netic testing to better understand individual risk remains a hot topic. "The major genetic markers for AMD have been identified and their impact on AMD progression has been quantified," said Carl C. Awh, MD, Tennessee Retina P.C., Nashville. Patients at increased risk of AMD progression can be moni- tored more frequently and "may be more compliant with Amsler grid testing and nutritional supplement intake, and are the best candidates for new methods of identifying AMD progression, such as the ForeseeHome Preferential Hyperacuity Perimetry device [Notal Vision, Tel Aviv]," he said. As with genetic causes in any disease, "knowing the underlying genetic factors may open up new areas for research and opportunities for clinicians to understand more about the pathophysiology of AMD," said Justis P. Ehlers, MD, Cleveland Clinic, Ohio. Genetic information may also be used to select "the optimal nutri- tional supplement for patients with moderate AMD," Dr. Awh said, and may one day be used to predict response to current intravitreal treatments, "as demonstrated by the recent lampalizumab phase 2 results, where patients with complement factor I risk alleles had a superior response to an investigational treatment for geographic atrophy." There are two commercially available genetic tests for AMD risk; both calculate the risk of AMD pro- gression based on the presence of non-genetic (e.g., clinical stage of AMD, age, smoking history) and genetic risk factors. A third genetic test does not specifically interpret data to gauge AMD risk. Both the Macula Risk (ArcticDx, Grand Rapids, Mich.) and Retna- Gene (Sequenom, San Diego) tests are based on algorithms validated by large independent population studies, including the Age-Related Eye Disease Study (AREDS). The addition of genetic information to the clinical examination results in a predictive accuracy near 90%. Smoking and body mass index are also components of the Macula Risk test; the RetnaGene takes into account smoking status only. The Macula Risk PGx test is recom- mended for all patients with AMD, except for those with stage 1 disease (as defined by AREDS) who have no family history of AMD and are under 50 years old. The RetnaGene test was designed to identify Caucasian patients older than 55 years who are at risk of disease progression. Dr. Awh emphasized that AMD genetic tests are intended to comple- ment a careful clinical examination, not to replace it, and does not advo- cate genetic testing for individuals without AMD. "In the absence of detectable AMD, there is no demonstrated risk of AMD progression and no reason, at present, to obtain a genetic test," he said. "The clinical examination remains the foundation of how we determine the risk of AMD progres- sion. However, among individuals with the same clinical stage of AMD, there can be a substantial difference in progression risk due to differences in genetics. This improved under- standing of an individual's risk based on an objective laboratory re- sult allows us to more appropriately direct resources for each patient." What the AAO says In short, the American Academy of Ophthalmology (AAO) recommends its members "avoid genetic testing for complex eye disorders such as age-related macular degeneration and late-onset primary open angle glaucoma," until a time when such strategies "can be shown to be of benefit to individuals with specific disease-associated genotypes, and [AAO] urges medical personnel to confine the genotyping of such patients to research studies." At the 2012 AAO annual meet- ing, Edwin Stone, MD, head of the Academy's Genetic Testing Task Force, said that while it was inappro- priate at the time as "cost and risks far outweigh any benefit," he did not discount the potential for these tests into the future. Dr. Stone said that one of the main reasons for the current recom- mendation was that "none of the available genetic tests for AMD have been shown to improve the outcome of patients in a controlled clinical trial." Dr. Ehlers believes the AAO's recommendations must be strongly considered, and it is also important to keep patients informed regarding the current state of genetic testing in AMD. "More and more patients are coming into your office and asking about genetic evaluation. It is im- portant to be able to give them an idea of the potential upsides and downsides to testing," he said. Dr. Awh "agrees with much of the AAO Genetic Testing Task Force recommendations," but disagrees with the specific wording on the AMD testing, primarily because the Task Force stipulates that "treatment or surveillance strategies" must be shown in "one or more prospective clinical trials to be of benefit," he said, citing the lack of such trials for other commonly used diagnostic tools (optical coherence tomography and fluorescein angiography), or even other genetic tests (such as those for Mendelian disorders, which the AAO does endorse). What to tell patients Nutritional supplementation is often prescribed for those with moderate AMD, and typically the AREDS or AREDS2 formulations are recom- mended. Dr. Awh and colleagues have published data suggesting that indi- viduals with 2 CFH risk alleles and no ARMS2 risk alleles treated with zinc or with antioxidants plus zinc (the AREDS formulation) do worse than if treated with placebo. 1 In an analysis of 989 patients followed in the original AREDS, those with that combination of genetic risk who were assigned to the AREDS formulation had accelerated disease progression, with a 35% increase in the 12-year incidence of advanced AMD vs. no treatment. 1 Emily Chew, MD, deputy clini- cal director, National Eye Institute (NEI), Bethesda, Md., disagreed with those assumptions at a recent con- ference. In her presentation, she said the AREDS formulation "was never demonstrated to be beneficial with each component alone. Our recom- mendation is the combination of vitamins and zinc is best-proven in more than 4,000 participants." She added that the NEI's own analysis July 2014 by Michelle Dalton EyeWorld Contributing Writer Questions remain about genetic testing Device focus Test Brief description Sample Macula Risk (ArcticDx) Combined prognostic and pharmacoge- netic DNA test; 15 genetic markers across 12 AMD-associated genes Cheek swab RetnaGene (Sequenom) Genetic profile of 12 disease-associated single nucleotide polymorphisms Cheek swab 23andMe Over-the-counter genetic test providing data for 85 SNPs along the CFH gene, 8 SNPs on the ARMS2 gene and 50 SNPs on the C2 gene Saliva/cheek swab Currently available genetic tests. Note: 23andMe does not specifically test for AMD, and the company does not interpret the results. continued on page 24 12-29 News_EW July 2014-DL_Layout 1 6/30/14 8:38 AM Page 22

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