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Update on Genetics and Age-Related Macular Degeneration

Joshua Dunaief, MD, PhD

Scheie Eye Institute, University of Pennsylvania

  • Expert Advice
Published on:
An illustration of several DNA molecules.

Age-related macular degeneration (AMD) is caused by a number of genetic and environmental factors. People with an affected parent have approximately twice the risk of getting the disease than someone whose parents do not have AMD. Learn about the genes that increase the risk of AMD, and whether genetic testing is recommended.

Recent advances in gene sequencing and mutation-detecting technology have identified sequence changes in at least 19 genes that can increase the risk.

Two Genes Stand Out

Two genes increase the risk of AMD more than any of the others. These are called complement and ARMS2/HTRA.

Complement is an arm of the immune system that attacks invading bacteria. It is a series of proteins that recognize the bacteria as foreign, then initiate a cascade of events that pokes holes in bacterial membranes and recruits white blood cells to kill them. Complement can sometimes inappropriately target our own cells, including those in the retina. Among the complement genes, complement factor H confers the greatest AMD risk.

Not only is complement genetically associated with AMD, it also has been shown to be activated in the retinas of people with AMD. The activated proteins were found near the cells that are damaged in AMD, within deposits called drusen. This has led researchers and pharmaceutical companies to develop complement inhibitors to treat or prevent AMD. In one phase II trial, a drug called lampalizumab, injected into the eyes of people with the advanced dry form of AMD called geographic atrophy, appeared to protect the retina by slowing the growth of atrophy. Unfortunately, the phase III clinical trials with Lampalizumab failed to slow the rate of expansion of geographic atrophy.

Another complement inhibitor made by Apellis, which inhibits a different complement protein called C3, recently showed promising results in a Phase II trial.

While ARMS2/HTRA is the subject of intensive research, the role of these genes in AMD is not yet understood. Other genes that confer AMD risk include those involved in cholesterol metabolism, collagen production, and cell signaling. Similarly, the research on these genes is not as advanced as it is for complement.

Genetic Testing

Genetic testing is now available to assess some of the AMD risk genes. Once the information from this testing is shown to affect the choice of AMD treatment, it could be helpful to undergo the testing.

However, currently there are no studies firmly demonstrating that genetic testing should influence AMD treatment selection. Anyone with a family history of AMD should see an ophthalmologist and try to eat a diet rich in fruits and vegetables, fatty fish twice a week (salmon, tuna, sardines, mackerel), avoid a high red meat diet, and avoid smoking.

The Future

As DNA sequencing technology becomes cheaper and faster (currently the whole genome can be sequenced in a few days for $1000!), and information about the meaning of DNA sequence changes is advanced, it is likely that genetic testing will be more practical and helpful in guiding treatments for AMD and a growing list of other diseases.

About the author

Headshot of Dr. Joshua Dunaief

Joshua Dunaief, MD, PhD

Scheie Eye Institute, University of Pennsylvania

Joshua Dunaief, MD, received his BA magna cum laude in Biology from Harvard (1987), MD/PhD from Columbia College of Physicians and Surgeons (1996), completed ophthalmology residency at the Wilmer Eye Institute, Johns Hopkins in 2000, and medical retina fellowship at Scheie Eye Institute, University of Pennsylvania in 2004.

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