Investigations continue into the genetic influences of AMD

Dr. Ryan delivered the Founders Award Lecture at the American Society of Retina Specialists in Montréal.

"There are a number of hypotheses about the development of macular degeneration that include the processes of inflammation, oxidative damage, effects on the extracellular matrix, and cholesterol metabolism among others. We should consider these and other biologic mechanisms and the genetic control and predisposition to disease that underpins these mechanisms," Dr. Ryan said.

"The explosion of knowledge from the sequencing of the human genome makes all of these investigations feasible," emphasized Dr. Ryan, president of the Doheny Eye Institute, and Beardsley Professor of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles. "There are 3.3 billion base pairs organized into 22 chromosome pairs plus the X and Y chromosomes that are organized into about 30,000 genes, which translate and code for more than 500,000 proteins."

The genetic sequences of different people have been found to be remarkably similar, such that when the chromosomes of two individuals are compared, their DNA sequences can be identical for hundreds of bases. He demonstrated an example of the comparison of the DNA sequences of two randomly chosen individuals; there were only two differences among 2,200 nucleotides on chromosome 7. The common types of differences in the individual bases are the single nucleotide polymorphisms (SNPs). Identification of most of the estimated 10 million SNPs that occur within the genome will provide the basis for the large fraction of the genetic diversity of the human species.

AMD phenotypes

"An accurate description of AMD phenotypes from early AMD to geographic atrophy to CNV is key for the accurate correlation with the disease genotype. Clinically, retina specialists are able to distinguish a normal macula from early age-related maculopathy and can observe that some of these eyes progress to develop geographic atrophy and other eyes develop CNV leading to hemorrhage, and ultimately, a disciform scar. Retina specialists have learned a great deal clinically from histopathologic correlations," Dr. Ryan said.

"Recent advances in imaging technologies, particularly the development of digital image capture and optical coherence tomography (OCT) to supplement conventional photography and angiography, have created the potential to classify disease phenotype more accurately for correlation with genetic predisposition," he said.

Dr. Ryan emphasized that it was critical for retina specialists to take advantage of these new technologies to develop more precise, objective, and reproducible definitions of disease to supplant the subjective, qualitative, and categorical classification of disease that has been used in clinical practice to date. As an example, Dr. Ryan cited the importance of the morphology and number of drusen in the staging of macular degeneration, and how improved quantification and classification of drusen could enhance genotypic correlation.

There is a genetic predisposition for patients to develop CNV. Biologic processes such as inflammation and angiogenesis that are influenced by genetic predisposition are key components in the development of CNV or "wet" AMD. The complement factor H gene was recently identified by four separate groups as associated with the risk of the development of AMD.^1-4

"However, in patients who develop geographic atrophy, apoptotic pathways leading to cell death may also have a genetic basis," Dr. Ryan said. He noted the striking differences in disease phenotype between populations such as in Iceland where geographic atrophy accounts for about 75% of the AMD⁵-just the reverse of that found in the United Kingdom and United States-consistent again with a genetic predisposition.