Early Detection and Treatment of AMD

How genetic testing can help you meet your goals.

Early Detection and Treatment of AMD

How genetic testing can help you meet your goals.


Genetic research has identified more than 10 loci associated with an increased risk of AMD. The availability of commercial genetic tests for AMD requires us to carefully consider the potential advantages and limitations of this information. Is there a role for genetic testing in the management of patients with AMD?

The American Academy of Ophthalmology has advised doctors to “avoid routine genetic testing for genetically complex disorders like age-related macular degeneration and late-onset primary open-angle glaucoma until specific treatment or surveillance strategies have been shown in one or more published clinical trials to be of benefit to individuals with specific disease-associated genotypes.”1 In addition, the genes associated with AMD progression have not consistently predicted a response to anti-VEGF therapy, suggesting the genes that influence response to therapy may differ from those that influence the onset of neovascular AMD.2-4

However, mounting evidence points to the ability of genetic testing to predict the risk of developing advanced AMD for selected patients who are in the early and intermediate stages of the disease. Here are some strategies for incorporating this important intervention into your practice.

Considering Risk Factors

Non-genetic risk factors for AMD progression are well known. The most significant non-genetic risk factor for AMD is of course age. The Beaver Dam Eye Study demonstrated that progression to any form of AMD in a 10-year period was 4.2% for persons aged 43 to 54 years and 46.2% for those 75 years of age and older.5 Another significant risk factor is smoking, which doubles the risk.6 Other possible risk factors include:

■ Hypertension and cardiovascular disease7,8

■ Low levels of anti-oxidants9

■ Higher intake of saturated fats and cholesterol and higher body mass index10

■ Higher markers of inflammation11

■ Sunlight exposure.12

The relative risk contribution of these factors is unknown. However, many doctors consider it prudent to advise patients with AMD to modify their diet or activities based upon findings from observational studies.

After a Diagnosis

Patients with early AMD should have periodic dilated eye examinations to detect progression to intermediate AMD.13 Patients with intermediate AMD, who are at increased risk of visual loss due to progression to advanced AMD, should be evaluated more frequently and should be educated about methods to detect symptoms of choroidal neovascularization (CNV).

Besides more frequent monitoring and the traditional Amsler grid, higher risk patients may also benefit from home monitoring devices. Preferential hyperacuity perimetry has been demonstrated to detect early neovascular AMD with greater sensitivity and specificity than the Amsler grid.14,15

When Genetic Testing Can Help

Patients with moderate AMD are probably the best candidates for genetic testing, because these are the patients for whom the results of a genetic test are most likely to influence management. Although phenotype is known to be the most important predictor of AMD progression, genetic testing can add to the value of the clinical examination. Con sider the work of Johanna Seddon, MD, and her colleagues. Using an AMD risk model that included age, gender, education, baseline AMD grade, smoking and body mass index, they plotted risk at 0.757 in the area under the curve (AUC).16 Adding genetic factors (SNPs in CFH, ARMS2, C2, CFB and C3) increased the AUC to 0.821. In these models, the baseline grade of AMD was the strongest predictor of risk of progression to advanced AMD.

Michael Klein, MD, and his colleagues confirmed that macular phenotype, represented by the AREDS Simple Scale score, had the greatest predictive value.17 They considered age, family history, smoking, the AREDS Simple Scale score, the presence of very large drusen, the presence of advanced AMD in one eye, and two polymorphisms in CFH and ARMS2 — factors that were strongly associated with risk of AMD. The AUC was 0.872 with genetic factors included and 0.865 without.

When interpreting these studies, we must remember that these data were derived from patients with phenotype determined by skilled grading of standardized color fundus photography, which is generally more accurate than staging by a typical clinical examination. Although nothing is more important than phenotype in the evaluation and management of patients with AMD, the additive value of a consistently reliable genetic test to an inconsistent clinical classification is probably greater than has been demonstrated in studies published to date.

Benefits of Early Detection

The combination of clinical assessment and genetic testing has been shown in clinical trials to provide the most accurate prediction of AMD progression.16,18 (See “Advancing AMD Genetics” for more details.)

The benefit of early detection for patients has been clearly demonstrated as well. In a 2007 analysis of a MARINA Study subgroup, more than half of wet AMD patients treated with ranibizumab failed to maintain functional vision in their first eyes after 2 years of treatment.19 Patients in the same study who were treated earlier in the course of the disease maintained near-normal vision (20/63 or better) approximately 90% of the time. Early detection leads to better final visual acuity.

Subsequent peer-reviewed publications have confirmed the benefits of early treatment and surveillance for high-risk patients.20,21 Furthermore, the 2008 AAO Preferred Practice Pattern has recommended “patients at high risk may be examined more frequently in an effort to detect asymptomatic CNV at a treatable stage.”

Advanced Disease Treatment

Treatment with antioxidants and minerals, based on the AREDS9 is recommended for patients who have progressed to intermediate or advanced AMD in one eye. AREDS 2 may soon produce additional recommendations.

AREDS 2 has enrolled 4,000 patients with non-neovascular AMD, consisting of large drusen in both eyes or advanced AMD in one eye and large drusen in the fellow eye. The goal of this trial is to evaluate the effect of dietary xanthophylls (lutein and zeaxanthin) and/or omega-3 long chain polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid) on progression to advanced AMD.

Given the demonstrated benefits of earlier detection and treatment of neovascular AMD, it seems logical to use the results of genetic testing to identify a subgroup of patients at particularly high risk of progression. These patients can be followed at a frequency and intensity that would be impractical for all patients with intermediate AMD. Moreover, the knowledge that a patient is at increased genetic risk is likely to influence his or her lifestyle choices, examination compliance and response to new symptoms.

Genetic tests for AMD continue to evolve. Their predictive power is increasing, and I believe that the thoughtful use of this revolutionary technology will lead to better outcomes for patients with AMD.

Dr. Awh is President of Tennessee Retina, PC, in Nashville, Tenn. He is an investor in and member of the scientific advisory board of ArcticDX, makers of the Macula Risk NXG test.


1. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology 2012;119(11):2408-2410.

2. 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 E-pub ahead of print: Jan. 18, 2013.

3. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr. Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2009;93(5):610-613.

4. Kloeckener-Gruissem B, Barthelmes D, Labs S, et al. Genetic association with response to intravitreal ranibizumab (Lucentis) in neovascular AMD patients. Invest Ophthalmol Vis Sci 2011;52(7):4694-4702.

5. Klein R, Klein BE, Tomany SC, et al. Ten-year incidence and progression of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 2002;109:1767-1779.

6. Khan JC, Thurlby DA, Shahid H, et al. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol 2006;90:75-80.

7. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107(12):2224-2232.

8. Hyman L, Schachat AP, He Q, Leske MC. Age-Related Macular Degeneration Risk Factors Study Group. Hypertension, cardiovascular disease, and age-related macular degeneration. Arch Ophthalmol 2000;118:351-358.

9. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report number 9. Arch Ophthalmol 2001;119:1439-1452.

10. Clemons TE, Milton RC, Klein R, et al. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS). AREDS report number 19. Ophthalmology 2005;112:533-539.

11. Seddon JM, George S, Rosner B, Rifai N. Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123:774-782.

12. Khan JC, Shahid H, Thurlby DA, et al. Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight. Br J Ophthalmol 2006;90:29-32.

13. Preferred Practice Pattern. Age-Related Macular Degeneration. American Academy of Ophthalmology, 2008.

14. Alster Y, Bressler NM, Bressler SB, Brimacombe JA, et al; Preferential Hyperacuity Perimetry Research Group. Preferential Hyperacuity Perimeter (PreView PHP) for detecting choroidal neovascularization study. Ophthalmology 2005 112:1758-1765.

15. Lai Y, Grattan J, Shi Y, Young G, Muldrew A, Chakravarthy U. Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter. Retina 2011;31:1620-1626.

16. Seddon JM, Reynolds R, Maller J, Fagerness JA, et al. Prediction model for prevalence an incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50(5):2044-2053.

17. Klein ML, Francis PJ, Ferris FL 3rd, Hamon SC, Clemons TE. Risk assessment model for advanced age-related macular degeneration. Arch Ophthalmol 2011;129(12):1543-1550.

18. 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(3):1548-1556.

19. Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007;114(2):246-252.

20. Lim JH, Wickremasinghe SS, Xie J, et al. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol 2012;153(4):678-686.

21. Maguire MG, Alexander J, Fine SL, Complications of Age-related Macular Degeneration Prevention Trial (CAPT) Research Group. Characteristics of choroidal neovascularization in the complications of age-related macular degeneration prevention trial. Ophthalmology 2008;115(9):1468-1473.