Study identifies gene associated with geographic atrophy

Double-strand viral RNA can activate the receptor, especially in patients at high risk for dry age-related macular degeneration.

One gene may play a key role in the development of dry age-related macular degeneration, according to new research.

The study demonstrated the role that the toll-like receptor 3 gene (TLR3) plays in causing cell death, a catalyst of geographic atrophy. In addition, the researchers found no correlation between TLR3 and wet AMD, Kang Zhang, MD, PhD, and colleagues reported in the New England Journal of Medicine.

“This is an important finding because this is the first gene identified specifically affecting geographic atrophy patients,” Dr. Zhang said in a telephone interview with Ocular Surgery News.

The findings may also lead to the development of TLR3 inhibitors to treat geographic atrophy, he said.

Geographic atrophy affects about 900,000 people in the United States. Its etiology is largely unknown, and it has no approved or effective treatment.

The authors cited earlier studies on possible associations between the toll-like receptor 4 gene (TLR4) and AMD. They then tried to determine associations between TLR3 variants and different types of AMD: soft, confluent drusen, choroidal neovascularization or geographic atrophy.

“TLR4 is a cousin of TLR3,” Dr. Zhang said. “In addition, because TLR3 has been shown to cause atrophy or cell death in certain cells, we thought that it would be a good candidate to look at its potential association with AMD. … From there, we were able to show that indeed there were associations between the two.”

Case-controlled series

Researchers looked for associations between various AMD phenotypes and two potentially functional TLR3 variants: single-nucleotide polymorphisms (SNPs) rs5743303 and rs3775291.

The first case-controlled series for AMD included Americans of European descent from Utah: 441 patients with CNV, 232 with geographic atrophy, 152 with soft, confluent drusen and 359 normal controls without any signs of early AMD. Researchers found no significant association between SNP rs5743303 and any AMD phenotype, according to the abstract.

However, researchers found a strong association between the non-synonymous coding SNP rs3775291 and protection against geographic atrophy (P = .005), the authors said.

To replicate the SNP-AMD association, researchers undertook an independent case-controlled series of Americans of European descent (271 patients with geographic atrophy, 179 with CNV and 421 healthy controls). Researchers found a strong correlation between rs3775291 and geographic atrophy. However, they found no association between the TLR3 variants and CNV.

In a second test to reproduce the results, researchers performed a case-controlled series of patients of European descent from the Age-Related Eye Disease Study, including 184 patients with geographic atrophy and 134 controls. The test showed a strong correlation between rs3775291 and geographic atrophy, the authors reported.

Combined analysis of the three case-controlled series also showed a strong association between rs3775291 and geographic atrophy.

Viral factors, targeted therapies

Any double-strand RNAs, including viral RNAs, may contribute to geographic atrophy. In addition, short-interfering RNA therapies in the eye may have toxic side effects. Dr. Zhang said virus RNA may activate TLR3 and trigger a “suicide response” in affected cells that leads to cell death.

“Obviously, it’s a great strategy in terms of fending off viral infections,” he said. “However, in this case, it can also trigger cell death and degeneration of the macula, causing dry forms of macular degeneration. It’s sort of a double-edge sword.”

Specifically, double-strand RNA types can activate the TLR3 receptor, especially in patients who are genetically susceptible to geographic atrophy, Dr. Zhang said.

“In the next few years, the genetic research should provide a highly predictive value for telling which patients will have macular degeneration,” he said. “Hopefully, we’ll also be able to tell which patients will develop geographic atrophy vs. wet AMD.”

Ongoing research may also help researchers develop genetically targeted treatments for geographic atrophy.

“The future is bright,” Dr. Zhang said. “In 5 to 10 years, we hope to have effective treatment for both wet and dry macular degeneration.”

For more information:

• Kang Zhang, MD, PhD, can be reached at Shiley Eye Center, University of California San Diego, 9415 Campus Drive, La Jolla, CA 92037; 858-246-0440; e-mail: kangzhang@ucsd.edu. Dr. Zhang has an equity interest in Navigen, receives grant support and lecture fees from Genentech and consulting fees from Acucela and Oxigene.

Reference:

• Yang Z, Stratton C, et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration [published online ahead of print Aug. 27, 2008]. N Engl J Med. 2008; 359(14):1456-1463.

• Matt Hasson is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses on regulatory, legislative and practice management topics.