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Genetic Testing forMacular Degeneration
Edwin M. Stone, M.D., Ph.D.
The Howard Hughes Medical InstituteThe University of Iowa Institute for Vision Research
US Population over 75 years(will increase 44% by 2025)
From the US Census Bureau
19 million in 2012 27 million in 2025
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
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
• There is no mechanism-specific therapy available
• None of the tests can reliably distinguish between dry AMD and CNV
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)
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.
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.
Statistics
Normal vs AMD Dry vs CNVCompany 1 p = 1.4 x 10-5 p = 0.81 (NS)Company 2 p = 2.9 x 10-5 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.