July 2013, Issue 59

Genetic Testing for AMD

Ivana K. Kim, MD Associate Professor of Ophthalmology Harvard Medical School, Mass Eye and Ear Infirmary

The accumulation of knowledge regarding genetic risk factors for age-related macular degeneration (AMD) over the past decade has opened the opportunity for clinical genetic testing. Since the discovery of key polymorphisms in the region of complement factor H on chromosome 1 as well as the region of chromosome 10q26, numerous groups have investigated potential correlations between genotype and various clinical manifestations of AMD. The phenotypic characteristics examined for association with genotype have included disease progression, subtypes of neovascular disease, and response to treatment.^1-5

The association between genetic variants and risk of AMD progression is consistently strong and provides the basis for currently available genetic tests designed to predict an individual's risk of progression to advanced AMD. Clinical findings associated with risk of advanced AMD have been well established, and macular phenotype remains the strongest predictor of disease progression.^6,7 The incorporation of phenotype into the models of risk prediction employed by the newest versions of genetic tests for AMD increases the accuracy and clinical relevance of such testing. For example, based on phenotype alone, a patient with a score of 4 on the AREDS Simplified Severity Scale (e.g. large drusen and pigmentary changes in both eyes), would be predicted to have approximately a 50% chance of developing advanced AMD in one eye over 5 years.⁸ However, with the addition of genotyping data, the risk might range from 13% to 60% depending on the patient's genetic profile.⁹

The two tests designed to predict risk of advanced AMD using genotype combined with phenotype are Sequenom's RetnaGene and Macula Risk NXG from ArcticDx. The RetnaGene model utilizes 12 SNPs in the CFH region, C2, CFB, C3, and ARMS2, phenotype based on the AREDS Simplified Severity Scale, patient age, and smoking history to predict risk of neovascular AMD. Macula Risk NXG incorporates 15 SNPs in CFH, CFI, C3, C2, CFB, LIPC, ABCA1, CETP, ARMS2, and COL8A1, the phenotypic features of drusen size and presence of advanced AMD, as well as age, smoking history, and body mass index. The Macula Risk algorithm predicts risk of advanced AMD in general, not specifically neovascular AMD. Both tests have been validated through studies using the AREDS dataset.

When considering incorporating these tests into clinical practice, we must consider the patient population for which the results would be most beneficial. Since phenotype is the strongest predictor of progression, genetic profile minimally differentiates risk of progression in patients with early stages of AMD. Therefore, there is little utility in performing genetic testing for individuals with no or minimal clinical evidence of AMD. However, for those with high-risk clinical characteristics, genetic testing can result in significant divergence of predicted risk. In the validation study conducted by Sequenom, for those with an AREDS Simplified Severity Score of 3, risk of progression to neovascular AMD could vary from 10% to 48% at 5 years depending on genotype.⁹

Other factors to consider when ordering genetic testing include patient ethnicity. Since the models utilized in the currently available genetic tests for AMD have been developed and validated based on data from Caucasian populations, it is unknown how reliable these tests are in predicting risk in patients of other ethnic backgrounds. In addition, these tests have been designed to predict progression to advanced AMD and not to differentiate AMD from other maculopathies. As such, they should not be used for diagnostic purposes.

The role for genetic testing in management of AMD continues to evolve. Current tests allow for identification of patients at highest risk for advanced disease and may allow for prevention of vision loss by earlier detection of neovascular AMD. Additionally, those individuals determined to be at high risk of advanced AMD based on genetic testing may be more inclined to adopt preventative behaviors (e.g. smoking cessation, use of AREDS supplements) as indicated by studies in patients with Alzheimer's disease.¹⁰ However, whether implementation of genetic testing actually results in improved visual outcomes remains to be proven. Additionally, genetic testing does not currently play a role in therapeutic decisions because a definite correlation between genotype and response to current therapies has not been demonstrated. However, such associations may be identified in the near future – either as a result of newly appreciated genetic variations relevant to AMD or new therapies that target pathways elucidated by genetic risk factors.

References:
1. Seddon JM, Reynolds R, Yu Y, et al. Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors. Ophthalmology 2011;118:2203-2211.
2. Brantley M, Edelstein S, King J, et al. Clinical Phenotypes Associated with the Complement Factor H Y402H Variant in Age-related Macular Degeneration. Am J Ophthalmol 2007;144:404-408.e1.
3. Andreoli MT, Morrison MA, Kim BJ, et al. Comprehensive Analysis of Complement Factor H and LOC387715/ARMS2/HTRA1 Variants With Respect to Phenotype in Advanced Age-Related Macular Degeneration. Am J Ophthalmol 2010;148:869-874.
4. 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;115:1019-1025.
5. Hagstrom SA, Ying G-S, Pauer GJT, et al. Pharmacogenetics for Genes Associated with Age-related Macular Degeneration in the Comparison of AMD Treatments Trials (CATT). Ophthalmology 2013;120:593-599.
6. Klein ML. Risk Assessment Model for Development of Advanced Age-Related Macular Degeneration. Arch Ophthalmol 2011;129:1543.
7. Seddon JM, Reynolds R, Maller J, et al. Prediction Model for Prevalence and Incidence of Advanced Age-Related Macular Degeneration Based on Genetic, Demographic, and Environmental Variables. Investigative Ophthalmology & Visual Science 2009;50:2044-2053.
8. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 2005;123:1570-1574.
9. Perlee LT, Bansal AT, Gehrs K, et al. Inclusion of Genotype with Fundus Phenotype Improves Accuracy of Predicting Choroidal Neovascularization and Geographic Atrophy. Ophthalmology 2013 Mar 20. Epub ahead of print.
10. Chao S, Roberts JS, Marteau TM, et al. Health behavior changes after genetic risk assessment for Alzheimer disease: The REVEAL Study. Alzheimer Dis Assoc Disord 2008;22:94-97.