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

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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

Financial Interests to Disclose

None

AMD Prevalence 35% > Age 75

US Population over 75 years(will increase 44% by 2025)

From the US Census Bureau

19 million in 2012 27 million in 2025

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

• There is no mechanism-specific therapy available

• None of the tests can reliably distinguish between dry AMD and CNV

ARMS2

Normal vs AMD, p = 1.1 x 10-23

Dry vs CNV, p = 0.29 (NS)

High Risk Het Low Risk

Complement Factor H

Normal vs AMD, p = 3.8 x 10-19

Dry vs CNV, p = 0.36 (NS)

High Risk Het Low Risk

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.