Why Second-Generation Genetic Tests are Better

Non-genetic and genetic factors strengthen the data used to determine risk.

BY IVANA K. KIM, MD

The recent release of second-generation genetic tests for risk of AMD refines our ability to predict risk of progression to advanced disease for patients with moderate AMD. Here is a brief overview of the testing and its implications.

Bringing in the New

First-generation tests, which did not incorporate clinical findings, required clinicians to independently interpret genetic risk in the context of the clinical examination. It was difficult to precisely know how to weigh the various factors involved in risk assessment. The second-generation tests request specific clinical information so factors such as body mass index, history of smoking, and most importantly, macular phenotype, are formally incorporated into the risk calculation models.

The two leading tests available to help us stratify risk for advanced AMD are Macula Risk NXG (ArcticDx) and RetnaGene (Sequenom). Below is a description of each.

Macula Risk NXG: Like its first-generation predecessor, this test analyzes major genetic markers, including Complement Factor H, ARMS2 and Complement Component 3. It also utilizes seven other markers of AMD risk confirmed through recent research, including the cholesterol metabolic markers (CETP, LIPC, ABCA1 and APOE), the complement factor I gene (CFI), and both the tissue inhibitor metalloproteinase gene (TIMP3) and the collagen type 8 alpha I gene (COL8A1) from the extracellular matrix pathway.¹ Macula Risk NXG also tests polymorphisms in Complement Component 2 and Complement Factor B. In total, Macula Risk NXG genotypes 15 single nucleotide polymorphisms (SNPs) on 12 genes.²

Besides requesting information about drusen size and presence of CNV or geographic atrophy in each eye, the test requires physicians to provide smoking history and the patient’s height and weight, enabling calculation of body mass index. The DNA sample is obtained through a cheek swab. The results predict an individual’s risk of progression to advanced AMD within 2, 5 and 10 years, and patients are categorized into one of five risk groups (with five representing highest risk).

RetnaGene: This test is designed for predicting risk of wet AMD in Caucasian patients, 55 years of age or older, who already have signs of early or intermediate AMD. The new version of this test incorporates macular phenotype (expressed as the AREDS Simple Scale Score,3 age, and smoking history along with genotyping of 12 SNPs on 8 genes. The risk of progression to CNV in 2, 5, and 10 years is calculated, and the patient is categorized as high, moderate, or low risk. The DNA analysis is also done on cheek swabs.

Most Important Factors

The clinical status of the macula, i.e. findings such as large drusen, pigment alterations, or advanced disease in the fellow eye, is the strongest predictor of whether a patient will develop advanced disease. The incorporation of such phenotypic characteristics into genetic testing now allows us to more precisely see the added contribution of genotyping to risk prediction and makes the tests more clinically meaningful. For example, prior to the availability of current genetic tests, we would predict that a patient with CNV in one eye and large drusen in the other might have a 25% risk of progressing to advanced AMD in the second eye.3 With the addition of genetic testing, the predicted risk could vary from about 10% to 60%.⁴

The recommendations of the American Academy of Ophthalmology Task Force on Genetic Testing, which discourage against routine genetic testing for genetically complex disorders such as AMD, should be considered.⁵ However, judicious use of genetic testing in those patients most likely to benefit clinically (those with clinical findings indicating moderate risk of progression to advanced disease) may influence monitoring strategies and potentially prevent vision loss. In addition, the involvement of a trained physician, genetic counselor, or both, for all patients undergoing genetic testing should be encouraged, ensuring that appropriate interpretation and counseling are provided.

We are making progress toward more clinically meaningful genetic testing. As its use is further explored by thoughtful, knowledgeable physicians, its role in management of AMD may continue to expand.

Dr. Kim is Associate Professor of Ophthalmology at Harvard Medical School and on the Retina Service at Massachusetts Eye and Ear Infirmary.

References

1. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 2009;50(5):2044-2053.

2. Yu Y, Reynolds R, Rosner B, Daly MJ, Seddon JM. 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(3):1548-1556.

3. Age-Related Eye Disease Study Research Group. A Simplified Severity Scale for Age-Related Macular Degeneration: AREDS Report No. 18. Arch Ophthalmol 2005;123:1570-1574.

4. Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B. Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors. Ophthalmology 2011;118(11):2203-2211.

5. 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(11):2408-2410.