Age-related macular degeneration is a leading cause of irreversible visual loss throughout the developed world. The etiology of AMD involves a complex interaction of inflammatory, oxidative, degenerative, and genetic components. The field of human genomics has fostered significant advancements in our knowledge of the genetic basis of AMD.1 Recent developments in genetic testing have enabled ophthalmologists, optometrists, and even the consumer to order tests that assess AMD risk. Is there a role for genetic testing in AMD management? This article reviews the genetic basis of AMD, commercially available genetic tests for AMD, and the current evidence regarding the pharmacogenetics of AMD.2,3
AMD is not a monogenic disease caused by a single gene defect, but a complex disease with numerous genetic and environmental risk factors. Environmental risk factors include age, smoking, dietary nutrients, exogenous estrogen use, and others.4 The genetic component of AMD risk has been estimated at 70%.5 To date, 34 genetic loci encompassing 52 gene variants have been associated with AMD; it has been estimated that these 52 variants collectively account for about half of the heritability of the disease.1
Of the gene variants associated with AMD, the two most widely studied and important, due to their large effect sizes and relatively high frequencies in the population, are complement factor H (CFH)6-9 and age-related maculopathy susceptibility 2 (ARMS2).10,11 Most risk alleles are associated with both neovascular AMD and geographic atrophy, but a variant near MMP9 (matrix metalloproteinase-9) was recently identified as associated only with neovascular AMD. To date, this is the first neovascular-specific allele that has been identified.1
COMMERCIALLY AVAILABLE GENETIC TESTS FOR AMD
There are several commercially available genetic tests for AMD. In the United States, Macula Risk PGx (ArcticDx, Toronto) can be ordered by a provider. RetnaGene (Sequenom, San Diego) is no longer available. Asper Biotech based in Tartu, Estonia, offers direct-to-consumer genetic testing worldwide.
Prior to 2010, direct-to-consumer genetic AMD tests were an emerging market segment for the laboratory testing industry. Warning letters, however, issued by the FDA that year to Pathway Genomics Corporation (San Diego), deCODE Genetics (Reykjavik, Iceland), 23andMe (Mountain View, CA), and others stated that the offered tests met the definition of a medical device and, therefore, required FDA clearance or approval in order to be marketed to US consumers. The FDA argued that the tests had not been proved safe, effective, or accurate, and that patients could be put at risk by making medical decisions based on data that had not received independent market review.
Since that time, the above tests have been formally withdrawn from the direct-to-consumer marketplace, but a genetic AMD profile can still be obtained by the consumer indirectly from Promethease, a retrieval system that builds a personal DNA report based on connecting a file of DNA gene reports (from 23andMe and other US-based companies) to the scientific findings cited in SNPedia, a wiki for human genetics.
A macula risk test, ordered by an ophthalmologist, analyzes 15 variants across 12 loci and uses patient data such as age, body mass index, smoking history, and educational level, to stratify the patient into one of five “macula risk” categories that are associated with varying degrees of risk of progression to advanced AMD. The company offers a second test, “Vita Risk,” which uses variants at CFH and ARMS2 in an effort to predict response to nutritional therapy.
In 2002, a task force comprised of CDC and NIH researchers created the “ACCE” model to evaluate the utility of various genetic tests.12 The model considers four variables. Analytic validity measures the accuracy (sensitivity and specificity) with which the genetic information is detected. Clinical validity measures the extent to which the genetic test predicts the clinical phenotype. Clinical utility measures the ability of the test to improve clinical outcomes. The last variable describes the ethical, legal, and social implications of the test.
Applying the ACCE model to the Macula Risk test reveals that the test demonstrates analytic validity because it is technically accurate. One measure of the clinical validity of a predictive model uses area under the curve (AUC), in which an AUC of 0.5 or less indicates chance (no accuracy), an AUC of 1 is completely accurate, and an AUC of 0.75 or greater suggests a useful model.13 Models based on either clinical or genetic information may meet this definition of usefulness. For example, some clinical models with no genetic information have achieved AUCs of 0.76 or greater.14,15 Alternatively, some purely genetic risk models have achieved AUCs of 0.81 or greater.16,17 It is reasonable to suspect that models combining clinical and genetic data may yield even more accurate information, but this is not always the case. Combined models have reported AUCs of 0.75 or higher.18-24
The Macula Risk test is based on a statistical model with a reported AUC of 0.883 for five-year progression and 0.895 for 10-year progression, which suggests good clinical validity.25 However, one model incorporating only clinical data reported a similar AUC of 0.8815, suggesting that comparable validity may be achieved without any genetic analysis.
The clinical utility of the Macula Risk test is more controversial. One might recommend more frequent examinations for higher-risk patients, but there is little or no peer-reviewed evidence to support such a strategy. The utility of genetic testing for predicting response to nutritional supplementation is discussed in the next section.
The ethical, legal, and social implications of genetic testing may be considerable, especially if a genetic test is requested by a young, asymptomatic patient. For these reasons, the American Academy of Ophthalmology created a task force on genetic testing and published recommendations in 2012,26 which were updated in 2014. These recommendations support offering genetic testing to patients suspected of having a monogenic (Mendelian) disease and providing such patients with genetic counseling (or referring to a genetic counselor). The task force recommended avoiding direct-to-consumer genetic testing and avoiding routine testing of complex genetic diseases such as AMD.
AMD is most commonly managed with pharmacotherapies. Patients with neovascular AMD are generally treated with anti-VEGF agents, including ranibizumab (Lucentis, Genentech, South San Francisco, CA), aflibercept (Eylea, Regeneron, Tarrytown, NY), and bevacizumab (Avastin, Genentech).27 Additionally, patients with at least intermediate AMD are typically offered nutritional supplementation based on the results of the Age-Related Eye Disease study (AREDS)28 and AREDS 2 29 trials.
Small series have reported statistically significant associations between treatment responses to various anti-VEGF agents and variants in CFH, ARMS2, and other genes.30 To date, these findings have not been validated, and major randomized clinical trials have not reported any statistically significant associations.
The Comparison of AMD Treatments trials (CATT) compared patients with neovascular AMD treated with bevacizumab or ranibizumab and reported no significant association between various anatomic and visual outcomes and variants in CFH, ARMS2, HTRA1, and complement factor 3 (C3);31 endothelial PAS domain-containing protein 1 (EPAS1);32 and VEGF-A and VEGF receptor 2.33 Additionally, the Inhibit VEGF in Patients with Age-Related Choroidal Neovascularization (IVAN) study compared patients with neovascular AMD treated with bevacizumab or ranibizumab; it reported no significant association between central retinal thickness on optical coherence tomography and variants in CFH, HTRA1/ARMS2, EPAS1, and frizzled class receptor 4 (FZD4).34 Using pooled data from CATT and IVAN, the researchers found no significant association between mean change in visual acuity and VEGF receptor 2.35 Hong et al performed a systematic review and meta-analysis for investigation of the association of the polymorphism Y402H in the CFH gene with response to anti-VEGF treatment in AMD and concluded that Y402H might be a genetic predictor of treatment response to anti-VEGF therapy in AMD patients.36
Greater controversy exists regarding the potential pharmacogenetic relationship between AREDS nutritional supplementation and the risk of progression to advanced AMD (including neovascular AMD and central GA).37 AREDS categorized patients using a one to four scale in which categories one and two had mild disease; category three had at least one large (≥125 µm) druse, extensive intermediate (63-124 µm) drusen, and/or noncentral GA; and category four had central GA, neovascular AMD, and/or best corrected visual acuity less than 20/32 resulting from AMD in one eye. AREDS randomized patients to receive one of four treatments: antioxidants alone (beta-carotene, vitamin C, and vitamin E), zinc alone (zinc plus copper), antioxidants plus zinc, and neither (placebo). In patients with category three or four AMD, treatment with antioxidants plus zinc — which eventually became the AREDS formulation — was associated with an approximate 25% decrease in disease progression rates at 5 years. The AREDS Investigative Group collected genetic information from some participants, but did not incorporate this information into their reported findings.28
A retrospective subgroup analysis of 876 patients with category three or four disease from the AREDS trial compared outcomes of patients stratified by genotype at CFH and ARMS2. The investigators reported that all patients in this subgroup benefited from AREDS supplementation, but patients with no risk alleles at CFH experienced significantly more favorable outcomes than did patients with two risk alleles at CFH. There was no association with ARMS2. Despite the statistically significant association with CFH, the investigators did not recommend a change in treatment (because all patients experienced some benefit) and called for additional studies to corroborate the genetic findings.38
Another retrospective subgroup analysis on the same AREDS trial, this time involving 995 patients, was performed. These patients had AREDS category 3 disease in at least one eye.39 Researchers looked for associations between genotypes at CFH and ARMS2 and outcomes stratified by the four treatment categories (antioxidants, zinc, both, and neither). They reported the benefit of zinc-only supplementation in reducing progression to advanced AMD in subjects with no risk alleles for CFH and one or two ARMS2 risk alleles.39 The authors found that 49% of subjects analyzed derived more benefit from a supplementation regimen other than the AREDS formulation. The investigators concluded that a pharmacogenetic approach in which patients were assigned to nutritional supplementation based on genotypes at CFH and ARMS2 might lead to more favorable outcomes.39
Next, a subgroup of 1237 patients with category three or four disease from the same AREDS trial was investigated. Here, investigators reported no significant associations between progression rates stratified by nutritional supplementation and genotypes at CFH and ARMS2.40
Another study looking at CFH, ARMS2, and category three or four disease was initiated, this retrospective subgroup analysis involving 989 patients from the original AREDS trial.41 A complex relationship between CFH, ARMS2 was found, with outcomes stratified by nutritional supplementation. These authors concluded that “most” patients would benefit from either no supplementation or a supplementation other than AREDS formulation (antioxidants plus zinc). The recommendation was that patients be offered genotype-directed nutritional supplementation.41
An attempt to replicate the study that analyzed only a subset of the patients in the original AREDS trial could not be replicated. This study involved 525 patients. The investigators reported that, among the 526 patients analyzed, the AREDS formulation (antioxidants plus zinc) was the most beneficial nutritional supplement for all genetic subtypes studied.42 More recently, another group44 evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD using the eye as the unit of analysis. The authors considered 4,124 eyes in 2,317 AREDS subjects in their survival analysis and reported that among the antioxidant and zinc supplement users compared with placebo, subjects with the nonrisk genotype for CFH had a lower risk of progression to advanced AMD. No significant treatment effect was noted among subjects who were homozygous for the CFH risk allele. A protective effect of the combined supplementation was observed among high-risk ARMS2 carriers. The authors concluded that the effectiveness of antioxidant and zinc supplementation appears to differ by genotype, and they called for additional studies.44
To date, there has not yet been a prospective clinical trial that specifically has studied genotype-phenotype relationships with respect to nutritional supplementation or anti-VEGF therapy in AMD patients. Dr. Edwin Stone, an expert in ophthalmic genetics, published a special communication in JAMA Ophthalmology in May 2015 in which he wrote that improved outcomes for genotyped AMD patients have not yet been demonstrated in a prospective clinical trial and that the costs and risks of routine genetic testing currently outweigh the benefits in AMD patients.45 As noted above, the American Academy of Ophthalmology also recommends avoiding routine genetic testing for genetically complex disorders like AMD.26
AMD is a multifactorial disease with many genetic and environmental risk factors. Over the past decade, much insight has been gained regarding AMD risk variants, but at this time there is no convincing evidence that genetic testing is beneficial in the routine management of AMD patients. Data from future large, prospective trials may provide validation for the pharmacogenetics of AMD. At the present time, genetic testing is more useful as a research tool than in clinical management. RP
- Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48:134-143.
- Hampton BM, Kovach JL, Schwartz SG. Pharmacogenetics and nutritional supplementation in age-related macular degeneration. Clin Ophthalmol. 2015;9:873-876.
- Schwartz SG, Hampton BM, Kovach JL, Brantley MA Jr. Genetics and age-related macular degeneration: a practical review for the clinician. Clin Ophthalmol. 2016;10:1229-1235.
- Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL 3rd; Age-Related Eye Disease Study Research Group. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19. Ophthalmology. 2005;112:533-539.
- Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol. 2005;123:321-327.
- Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
- Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
- Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
- Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulator factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227-7232.
- Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77:389-407.
- Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992-993.
- Burke W, Atkins D, Gwinn M, et al. Genetic test evaluation: information needs of clinicians, policy makers, and the public. Am J Epidemiol. 2002;156:311-318.
- Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, van Duijn CM, Khoury MJ. The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet Med. 2007;9:528-535.
- Ying GS, Maguire MG, Complications of Age-Related Macular Degeneration Prevention Trial Research Group. Development of a risk score for geographic atrophy in Complications of the Age-Related Macular Degeneration Prevention Trial. Ophthalmology. 2011;118:332-338.
- Chiu CJ, Mitchell P, Klein R, et al. A risk score for the prediction of advanced age-related macular degeneration: development and validation in 2 prospective cohorts. Ophthalmology. 2014;121:1421-1427.
- Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Hum Genomics. 2011;5:420-440.
- Grassmann F, Fritsche LG, Keilhauer CN, Heid IM, Weber BH. Modelling the genetic risk in age-related macular degeneration. PLoS One. 2012;7:e37979.
- Klein ML, Francis PJ, Ferris FL III, Hamon SC, Clemons TE. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. 2011;129:1543-1550.
- Spencer KL, Olson LM, Schnetz-Boutaud N, et al. Using genetic variation and environmental risk factor data to identify individuals at high risk for age-related macular degeneration. PLoS One. 2011;6:e17784.
- Chen Y, Zeng J, Zhao C, et al. Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch Ophthalmol. 2011;129:344-351.
- Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118:2203-2211.
- Seddon JM, Reynolds R, Yu Y, Rosner B. Validation of a prediction algorithm for progression to advanced macular degeneration subtypes. JAMA Ophthalmol. 2013;131:448-455.
- Buitendijk GH, Rochtchina E, Myers C, et al. Prediction of age-related macular degeneration in the general population: The Three Continent AMD Consortium. Ophthalmology. 2013;120:2644-2655.
- 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.
- Yu Y, Reynolds R, Rosner B, Daly MJ, Seddon JM. Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. Invest Ophthalmol Vis Sci. 2012;53:1548-1556.
- Stone EM, Aldave AJ, Drack AV, et al. Recommendations of the American Academy of Ophthalmology task force on genetic testing. Available at: http://www.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d .
- Kovach JL, Schwartz SG, Flynn HW Jr, Scott IU. Anti-VEGF treatment strategies for wet AMD. J Ophthalmol. 2012;2012:786870.
- Age-Related Eye Disease Study Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
- Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005-2015.
- Schwartz SG, Brantley MA Jr. Pharmacogenetics and age-related macular degeneration. J Ophthalmol. 2011;2011:252549.
- Hagstrom SA, Ying GS, Pauer GJ, et al. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). Ophthalmology. 2013;120:593-599.
- Hagstrom SA, Ying GS, Pauer GJ, Huang J, Maguire MG, Martin DF; CATT Research Group. Endothelial PAS domain-containing protein 1 (EPAS1) gene polymorphisms and response to anti-VEGF therapy in the Comparison of AMD Treatments Trials (CATT). Ophthalmology. 2014;121:1663-1664.
- Hagstrom SA, Ying GS, Pauer GJ, et al. VEGFA and VEGFR2 gene polymorphisms and response to anti-vascular endothelial growth factor therapy: Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). JAMA Ophthalmol. 2014;132:521-527.
- Lotery AJ, Gibson J, Cree AJ, et al. 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.
- Hagstrom SA, Ying GS, Maguire MG, et al. VEGFR2 polymorphisms and response to anti-vascular endothelial growth factor therapy in age-related macular degeneration. Ophthalmology. 2015;122:1563-1568.
- Hong N, Shen Y, Yu CY, Wang SQ, Tong JP. Association of the polymorphism Y402H in the CFH gene with response to anti-VEGF treatment in age-related macular degeneration: a systematic review and meta-analysis. Acta Ophthalmol. 2016;94:334-345.
- Hampton BM, Kovach JL, Schwartz SG. Pharmacogenetics and nutritional supplementation in age-related macular degeneration. Clin Ophthalmol. 2015;9:873-876.
- 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.
- Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants plus zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-2323.
- Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. 2014;121:2173-2180.
- 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.
- 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.
- Wittes J, Musch DC. Should we test for genotype in deciding on age-related eye disease study supplementation? Ophthalmology. 2015;122:3-5. ELIMINATE
- Seddon JM, Silver RE, Rosner B. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol. 2016;1:1-7.
- Stone EM. Genetic testing for age-related macular degeneration: not indicated now. JAMA Ophthalmol. 2015;133:598-600.