Delaying Vision Loss

How genetic testing can help predict risk of advanced AMD, leading to critical interventions at an early stage.

BY LAWRENCE SINGERMAN, MD

Genetic testing in the setting of AMD has been the subject of much debate and discussion. Here, via a case history, I will briefly review the effects of testing in combination with clinical assessment.

Testing Up Close

Two leading tests can help access risk of AMD — the Macula Risk NXG test (ArcticDx Inc.) and the RetnaGene AMD test (Sequenom).

The Macula Risk NXG test combines genetics with non-genetic risk factors, including age, smoking history, body mass index, and the clinical status of AMD in both eyes. Test results categorize five risk groups, with group five representing the highest risk. Validated risk determination has shown test sensitivity and specificity greater than 80% and a 10-year predictive value of 0.8951.¹

Patients at highest risk for progression include those who are older than 65, have drusen present and have scored MR3, MR4 or MR5 on the test. ArcticDx determines risk scores using complex algorithms after receiving swabs from inside the patient’s cheek and forms that document non-genetic factors.

The RetnaGene AMD test evaluates 12 single-nucleotide polymorphisms (SNPs) located on eight genes. These SNPs, when combined, are associated with the risk of progression to choroidal neovascularization in patients with early or intermediate disease. One of each of the inherited alleles is associated with high disease susceptibility, compared with the average population, while the other is either neutral or protective. A person’s genetic risk depends on whether he or she has inherited zero, one or two copies of the high-risk allele. The test also considers phenotype, based on the simplified severity scale grade,3 as well as age and environment (smoking status).

Applying Genetics

Here’s a hypothetical case history that demonstrates genetic testing in the clinic. A 72-year-old obese white male with a 40 pack-year history of smoking presented with hypertension, a sedentary lifestyle, and a diet that included one to two servings of fruits and leafy vegetables per week. An eye examination revealed a large druse in his right eye and, in his left eye, pigment abnormality and an additional large druse.

The simplified clinical scale for defining risk categories determined that, in addition to signs of disease in both eyes, he had three factors for advanced AMD: old age, smoking history, and a body mass index of 35.5. These factors put him at an approximately 25 percent risk of developing advanced AMD over 5 years.²

A Macula Risk test determined that the patient was in the fourth highest of five risk groups. His calculated risk level for a diagnosis of advanced AMD at age 80 was between 41 and 54 percent (46.5 percent median).

Informed of this and with proper counseling, the patient underwent nicotine replacement therapy and weaned himself off of cigarettes. He began a moderate exercise program (morning walks), increased his consumption of fruit and leafy vegetables and began taking AREDS supplements. He also was provided with an Amsler grid and was educated on the need to inform his doctor at the first sign of any changes in his vision. Eye examinations were performed twice a year.

His clinical status and vision remained stable for 18 months. At the third visit, however, early signs of neovascular AMD appeared, indicating the need to begin anti-vascular endothelial growth factor treatment. Because of the early intervention, however, his vision was preserved at 20/40, the same vision he presented with after developing wet AMD 2 years earlier.

Part of the Whole Picture

As this case demonstrates, there clearly is a role for genetic testing in the care of patients with early and intermediate stages of AMD. This testing is not appropriate for young patients or in the absence of a diagnosis of AMD. However, the benefit of being able to predict those at high-risk of vision loss is significant for patients and their doctors.

Dr. Singerman is the founder of Retina Associates of Cleveland, Inc. Active in clinical research, he has been a principal investigator in more than 100 multicenter clinical trials sponsored by NIH and pharmaceutical companies.

References

1. 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.

2. 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.