Genetic testing for AMD takes step in direction of individualized care

November 1, 2014

Selective genotyping allows clinicians to implement individualized surveillance programs that may increase the detection of progression and decrease the burden of unnecessary frequent examinations.

By Evelyn X. Fu, MD, Special to Ophthalmology Times

University Place, WA-Advanced age-related macular degeneration(AMD) is characterized by choroidal neovascularization (64%) and central geographic atrophy (36%).1 Although advanced AMD impacts only about 10% of the AMD disease population, it accounts for more than 90% of vision loss associated with this condition.2

Anti-vascular endothelial growth factor (VEGF) therapies have been proven effective in stabilizing and/or reducing vision loss associated with choroidal neovascularization (CNV) in some patients. Treatment regimes for central geographic atrophy (GA) have shown promising early results.3

More in this issue: Microscope-integrated OCT provides 3-D images in real-time

Therefore, timely diagnosis and treatment of CNV is critical in minimizing the irreversible vision-loss associated with treatment delay.4-6

Previously, age, ethnicity, smoking history, and phenotypical characteristics have been the main factors used in identifying patients with high risk of advanced AMD.7-14

However, not all patients within a demographic and phenotypic group have the same risk of advanced AMD progression.

For example, a patient with an Age-Related Eye Disease Study (AREDS) Simplified Severity Scale Grade III-which is relatively high risk-may have between a 70% to 90% risk of conversion to wet AMD within 10 years. A different patient with the same grade may only have a 15% to 30% risk of conversion based on genetic influence. (See graph)

Risk assessment purely based on demography and phenotype is limiting and ignores the importance of genetic predisposition.

Practical testing benefits

Selective genotyping allows clinicians to implement individualized surveillance programs that may increase the detection of progression and decrease the burden of unnecessary frequent examinations.


For example, patients who have minimal phenotypical ocular changes (AREDS Simplified Severity Scale Grade I) are often monitored annually or semi-annually.

However, patients with high genetic risks may benefit from more frequent examinations. These patients should also be extensively counseled on smoking cessation, weight loss, and healthier diet.

At the same time, they should be started on home vision monitoring programs using the traditional Amsler grid or various commercial applications currently available.

The results from genetic testing can be great motivators for behavior modifications.

On the other hand, patients who have moderate or severe phenotypical changes (AREDS Simplified Severity Scale Grade III and IV) are often monitored very closely-some on a quarterly basis.

These frequent examinations may not be necessary in all of these patients. Surveillance can be tailored in those with low-genetic risks to decrease the burden of frequent visits.

Patient selection,consultation

Genetic testing is not warranted in every patient with AMD. I currently consider testing in three groups of patients:

1. Patients with risky lifestyle behaviors, such as smoking.

2. Patients with moderate or severe phenotypic findings (Simplified Severity Scale Grade III or IV).

3. Patients with first-degree relatives affected by advanced AMD.

My approach to recommendation begins with educating patients about the pathogenesis and natural history of AMD. Although phenotyping has been invaluable in assessment, up to 71% of one’s risk of advanced AMD is influenced by genetics.15


I explain how the results may affect their surveillance regime and treatment recommendations. Patients are provided with extensive reading materials and asked to consider carefully the cost and implications of a laboratory-developed test (Retna­Gene, Nicox). If the patient is interested, he or she contacts the practice and schedules a time to undergo testing.

When the patient presents for testing, a technician completes a test requisition form, collects the DNA sample using a buccal swab, places labels on the tube and test requisition form, and prepares the swab for shipping on the same day.

I follow up with the patient 2 weeks after sample submission when the results become available. At this appointment, I explain the testing results, recommend lifestyle changes, and outline a surveillance protocol.

I have found that genetic testing results motivate behavior changes in patients with poor lifestyle choices and increase compliance with surveillance regimes. Monitoring schedules are implemented based on the patient’s individual risk.

Additionally, these encounters are used to educate patients regarding home vision monitoring and to stress the importance of early medical attention with any visual loss.

It is hoped that these efforts will decrease the incidences of patients erroneously attributing visual changes from AMD progression to other unrelated causes, such as cataract or ptosis.


Patient selection in genetic testing is crucial. The American Academy of Ophthalmology has recommended against the routine use of genetic screening in AMD.16

The utility of genetic screening is particularly limited in asymptomatic patients without known risk factors.

However, directed testing in a subset of the AMD patients with the highest risk of visual loss allow the ophthalmologists to develop individualized management protocols that may motivate behavior modification, increase surveillance compliance, and promote early detection.


Evelyn X. Fu, MD, is a retinal surgeon at Cascade Eye and Skin Centers, University Place, WA. Dr. Fu is a speaker for Nicox Inc. She may be reached at




 1. Tomany SC, Wang JJ, van Leeuwen R, et al. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology. 2004;111:1280–1287.

 2. AMD Alliance International. Basic facts about AMD. [Accessed Feb. 4, 2013]; Available at:

 3. Hariri A, Nittala M, Sadda S, et al. Outer retinal tubulation as a predictor of the growth rate of geographic atrophy in age-related macular degeneration. ARVO Meeting Abstracts. May 8, 2014;5885:C0071.

 4. 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;153:678–686.

 5. Muether PS, Hoerster R, Hermann MM, et al. Long-term effects of ranibizumab treatment delay in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. In press. 

 6. Muether PS, Hermann MM, Koch K, Fauser S. Delay between medical indication to anti-VEGF treatment in age-related macular degeneration can result in a loss of visual acuity. Graefes Arch Clin Exp Ophthalmol. 2011;249:633–637.

 7. 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.

 8. 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.

 9. McCarthy LC, Newcombe PJ, Whittaker JC, et al. Predictive models of choroidal neovascularization and geographic atrophy incidence applied to clinical trial design. Am J Ophthalmol. 2012;154:568–578.

10. Grassmann F, Fritsche LG, Keilhauer CN, et al. Modelling the genetic risk in age-related macular degeneration. [Accessed Feb. 4, 2013];PLoS ONE. 2012 7:e37979. Available at:

11. Yu Y, Reynolds R, Rosner B, et al. 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.

12. 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(3):e17784. doi: 10.1371/journal.pone.0017784.

13. 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.

14. Seddon JM, Reynolds R, Rosner B. Associations of smoking, body mass index, dietary lutein, and the LIPC genetic variant rs10468017 with advanced age-related macular degeneration. [Accessed Feb. 4, 2013];Mol Vis [serial online] 2010 16:2412–2424. Available at:

15. Seddon JM, Cote J, Page WF, et al. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol. 2005;123:321-327.

16. 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;119:2408-2410.