Evaluating both the genomic and proteomic biomarkers combined seems the most effective method to determine age-related macular degeneration risk and the likelihood of progression to advanced AMD.
The greatest future challenge is the development of a blood test to identify individuals who will develop AMD before any signs of the disease become apparent, according to Stephanie Hagstrom, PhD, who spoke during retina subspecialty day at the annual meeting of the American Academy of Ophthalmology.
In order to develop methods that better predict the patients who are susceptible to AMD, Dr. Hagstrom and colleagues have evaluated the combined predictive capability of genomic and proteomic biomarkers.
Complement components already have been identified in drusen, and a number of genetic studies have reported significant associations between AMD and DNA variants involved in the complement-associated pathway. Major breakthroughs in research during the past 5 years have shed a great deal of light on AMD and have affected the diagnosis, treatment, and management of the disease, she pointed out.
Single nucleotide polymorphisms have been shown to be strongly associated with the risk of AMD and protection.
"Many of these factors are within the cellular components of the retina, such as the photoreceptor cells, the retinal pigment epithelium, and the choriocapillaris," she said. "A number of these also have been identified in the acellular components, such as drusen."
Despite the great effect of the identified genes on the risk of AMD, a combination of the genes alone cannot correctly predict the development and progression of AMD in all cases.
A direct link between oxidative stress and the development of AMD was found with the discovery by Dr. Hagstrom's colleague, John Crabb, PhD, that the concentration of carboxyethylpyrrole (CEP) adducts, an oxidative protein modification generated from docosahexaenoic acid (DHA), is elevated in Bruch's membrane and drusen. The combination of high exposure to environmental light and high oxygen tension from the choriocapillaris is the perfect setting for the generation of reactive oxygen capable of damaging DHA, a highly oxidizable fatty acid concentrated in the photoreceptor cells.
"Modifications in CEP are generated by covalent adduction of primary amino groups on DHA," Dr. Hagstrom said. "When generated, the oxidative fragments condense with amino groups on protein and become deposited in Bruch's membrane, the choroid, the retinal pigment epithelial cells, and drusen."
Such changes are thought to be antigenic and a source of inflammatory signal to initiate the pathology of AMD.