Genetic Testing for Age-related Macular Degeneration
Age-related macular degeneration (AMD) is one of the most genetically characterized of all polygenic diseases, with more than 30 genetic loci identified and accounting for a substantial proportion of the heritability.1 The discovery of genetic polymorphisms in AMD not only provided important insights into the disease pathogenesis, but also promises to change clinical practice.
Genetic polymorphisms may permit risk stratification and prediction of response to therapies such as anti-vascular endothelial growth factor (anti-VEGF) treatment. Genetic information also may improve the ophthalmologist’s ability to predict progression to the advanced forms of AMD, choroidal neovascularization and geographic atrophy, above and beyond the information garnered from macular findings and demographic and behavioral risk factors such as age, gender, smoking, and education. For example, the genetic component of a risk prediction model with 10 single nucleotide polymorphisms (SNPs) in eight different genes added approximately 10 percent to the ability to predict AMD progression when compared to a model with macular phenotypes and demographic/environmental risk factors alone.2
While there has been extensive genetic discovery and excellent risk prediction models developed thus far in AMD, no prospective studies to date have proven that predicting increased disease risk will make a difference in AMD patient outcomes. In 2014, the American Academy of Ophthalmology (AAO) published recommendations for genetic testing of AMD, and specifically recommended to “avoid routine genetic testing for genetically complex disorders like AMD … until specific treatment or surveillance strategies have been shown in one or more published prospective clinical trials to be of benefit to individuals with specific disease-associated genotypes.” There have been conflicting retrospective studies examining the influence of genotypes on treatment response to Age-Related Eye Disease Study (AREDS) nutritional supplementation,3-6 but no prospective studies. Large, well-powered trials have not shown a differential response of patients with wet AMD to intravitreal anti-VEGF agents according to genotype.7, 8
Prospective studies would be helpful to determine whether patients with various genotypes would benefit from interventions — such as more frequent in-office examinations, more rigorous home monitoring of disease, or counseling about the importance of behavioral modifications — given their increased genetic risk. If these interventions produce better patient outcomes, then more evidence would exist to justify clinical genetic testing. If certain genotypes were shown to be associated with differential outcomes to AMD therapies in prospective trials, then that would also support clinical genetic testing for AMD. In the absence of prospective study data, however, genetic testing does not yet play a clear role in AMD.
While there is currently insufficient evidence to justify physician-ordered genetic testing for patients with AMD, some patients may pursue genetic testing on their own. Ophthalmologists need to be aware of the tests available in order to be able to counsel patients appropriately about the results of such testing. Studies have shown that the results of these tests can vary widely among different commercial entities that offer them.9 In three tested individuals, the risk of AMD predicted by different commercial tests varied from a 1.6-fold difference for overall relative risk to an up to 12-fold difference for lifetime risk. A second study has also demonstrated the variability and lack of precision among the direct-to-consumer tests offered by various companies.10
In summary, evidence that knowledge of AMD patients’ genotypes will help ophthalmologists provide more effective care for those patients has not yet been demonstrated in any prospective trial. Additional research on this topic is underway and we hope that one day knowledge of the genetic make-up of patients with AMD will permit preventive and therapeutic regimens to be selected in a more personalized fashion and lead to better clinical outcomes.
Reference(s):1. Fritsche LG, Chen W, Schu M, et al; AMD Gene Consortium. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45:433-439, 439e1-439e2.
2. Seddon JM, Silver RE, Kwong M, Rosner B. Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates. Invest Ophthalmol Vis Sci. 2015;56:2192-2202. PMCIDPMC4405097.
3. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2015;122:162-169.
4. 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;120:2317-2323.
5. Chew EY, Klein ML, Clemons TE, Agron E, Abecasis GR. Genetic testing in persons with age-related macular degeneration and the use of the AREDS supplements: to test or not to test? Ophthalmology. 2015;122:212-215.
6. Chew EY, Klein ML, Clemons TE, et al; Age-Related Eye Disease Study Research Group. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. 2014;121:2173-2180.
7. Hagstrom SA, Ying GS, Pauer GJ, et al; Comparison of AMD Treatments Trials Research Group. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). Ophthalmology. 2013;120:593-599.
8. Lotery AJ, Gibson J, Cree AJ, et al; Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) Study Group. Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN Study. Ophthalmology. 2013;120:2637-2643.
9. Buitendijk GH, Amin N, Hofman A, van Duijn CM, Vingerling JR, Klaver CC. Direct-to-consumer personal genome testing for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;55:6167-6174.
10. Kalf RR, Mihaescu R, Kundu S, de Knijff P, Green RC, Janssens AC. Variations in predicted risks in personal genome testing for common complex diseases. Genet Med. 2014;16:85-91.