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
Financial Interests to Disclose
None
AMD Prevalence 35% > Age 75
US Population over 75 years
(will increase 44% by 2025)
19 million in 2012
27 million in 2025
From the US Census Bureau
Prevention is the Key
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
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.
Ophthalmology. 2012 Nov;119(11):2408-10
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
Current AMD genetic tests have not
been shown to improve clinical outcome.
• Less sensitive and specific than clinicians.
• No mechanism-specific therapy available.
• None of the tests can reliably distinguish
between dry AMD and CNV.
ARMS2
100%
90%
80%
70%
60%
Normal vs AMD, p = 1.1 x 10-23
Dry vs CNV, p = 0.29 (NS)
n = 646 AMD pts, 305 controls
NL
50%
Dry AMD
40%
CNV
30%
20%
10%
0%
Risk
Hom
High
Risk
Risk
Het
Het
LowWT
Risk
100%
90%
80%
70%
60%
Complement Factor H
Normal vs AMD, p = 3.8 x 10-19
Dry vs CNV, p = 0.36 (NS)
n = 646 AMD pts, 305 controls
NL
50%
Dry AMD
40%
CNV
30%
20%
10%
0%
Risk Hom
High
Risk
Risk
Het
Het
LowWTRisk
PIIR Study
(Pepose Institute, University of Missouri, Illinois Retina)
N. Holekamp, A. Almony, M. MacCumber
• 103 subjects were tested for free by two commercial
labs: Arctic Dx (Macula Risk®) and Sequenom CMM
(RetnaGene™ AMD)
• 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)
Genotyping Errors
• Arctic 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.
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.
Theorectical Perfect Test Risk Rank
100
90
80
70
60
50
Normal
40
Dry AMD
30
CNV
20
10
0
0
10
20
30
40
50
60
70
Theoretical Perfect Test Risk Rank
80
90
100
100
90
Company 2 Risk Rank
80
70
60
50
Normal
40
Dry AMD
30
CNV
20
10
0
0
10
20
30
40
50
60
Company 1 Risk Rank
70
80
90
100
100
90
Company 2 Risk Rank
80
70
60
Normal
50
R2 = 0.57
40
30
20
10
0
0
10
20
30
40
50
60
Company 1 Risk Rank
70
80
90
100
Dry AMD
CNV
Theorectical Perfect Test Risk Rank
100
90
80
70
60
50
Normal
40
Dry AMD
30
CNV
20
10
0
0
10
20
30
40
50
60
70
Theoretical Perfect Test Risk Rank
80
90
100
100
90
Company 2 Risk Rank
80
70
60
50
Normal
40
Dry AMD
30
CNV
20
10
0
0
10
20
30
40
50
60
Company 1 Risk Rank
70
80
90
100
Statistics
Company 1
Company 2
Normal vs AMD
p = 1.4 x 10-5
p = 2.9 x 10-5
Dry vs CNV
p = 0.81 (NS)
p = 0.74 (NS)
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.