1) Genetic testing for age-related macular degeneration (AMD) is not currently recommended for routine use because no specific treatments have been shown to benefit individuals based on their genetic profiles in clinical trials. 2) While over 50% of AMD is attributable to genetic factors like CFH and ARMS2 variants, current genetic tests are less accurate than clinical exams in detecting treatable dry AMD or wet AMD. 3) A study comparing two commercial genetic tests to clinical diagnoses found the tests could distinguish AMD from normal controls but not dry AMD from wet AMD, and one test failed to detect a common genetic variant.

1. Genetic Testing for
Macular Degeneration
Edwin M. Stone, M.D., Ph.D.
The Howard Hughes Medical Institute
The University of Iowa Institute for Vision Research

2. Financial Interests to Disclose
None

3. AMD Prevalence 35% > Age 75

4. US Population over 75 years
(will increase 44% by 2025)
19 million in 2012 27 million in 2025
From the US Census Bureau

5. Prevention is the Key

6. AMD is Genetic
• More than 50% of all AMD is attributable
to genetic factors
• Several genes, especially CFH and
ARMS2, have been significantly
associated with the development of AMD

7. The Role of Genetics
• Elucidate molecular mechanisms
• Create in vitro and animal models
• Enable novel mechanism-specific
presymptomatic therapies
• Identify patient populations for clinical
trials of these therapies

8. Ophthalmology. 2012 Nov;119(11):2408-10

9. Task Force Recommendation
Avoid routine genetic testing for genetically complex
disorders like age-related macular degeneration . . . 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. In the meantime, confine the genotyping of
such patients to research studies.
Ophthalmology. 2012 Nov;119(11):2408-10

10. Current AMD genetic tests have not
been shown to improve clinical outcome
• Less sensitive and specific than clinicians
• There is no mechanism-specific therapy
available
• None of the tests can reliably distinguish
between dry AMD and CNV

11. ARMS2
Normal vs AMD, p = 1.1 x 10-23
Dry vs CNV, p = 0.29 (NS)
High Risk Het Low Risk

12. Complement Factor H
Normal vs AMD, p = 3.8 x 10-19
Dry vs CNV, p = 0.36 (NS)
High Risk Het Low Risk

13. PIIR Study
(Pepose Institute, Illinois Retina)
N. Holekamp, A. Almony, M. MacCumber
• 103 subjects were tested for free by two commercial
labs: Artic Dx (Macula Risk) and Sequenom (RetnaGene)
• 97 subjects had sufficient genotypic and clinical
information for comparison
• 17/97 were normal controls (avg age 76.9 yrs)
• 33/97 had dry AMD (avg age 79.3 yrs)
• 47/97 had CNV (avg age 79.3 years)

14. Genotyping Errors
• Artic Dx failed to detect the CFH H3 haplotype in
any patients (this haplotype is present in about
30% of the population).
• There were no detectable genotyping errors in
the data provided by Sequenom.

15. Risk Comparison Method
• Patients were assigned a risk rank from 1
(mildest) to 97 (most severe) based on the risk
score assigned to them from each company.
• These risk ranks were compared to each other
and to the clinical phenotype assigned by the
investigators.

21. Statistics
Normal vs AMD Dry vs CNV
Company 1 p = 1.4 x 10-5 p = 0.81 (NS)
Company 2 p = 2.9 x 10-5 p = 0.74 (NS)

22. Conclusions
• Avoid routine genetic testing for AMD until
specific treatments have been shown in clinical
trials to be of benefit to individuals with specific
disease-associated genotypes.
• For now, the standard clinical examination is
more sensitive and specific for detecting
treatable disease than any genetic test.