Dry AMD gene found

The discovery of the first gene known to be associated with dry age-related macular degeneration (AMD) has significant implications for the prevention and treatment of the condition, according to a study published in the October 2, 2008 issue of the New England Journal of Medicine.

Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at Shiley Eye Center in the School of Medicine at the University of California, San Diego, US and colleagues from multiple research institutes examined the possibility of a relationship between the rs3775291 mutation of the functional toll-like receptor 3 gene (TLR3), which substitutes leucine (Leu) with phenylalanine (Phe) at amino acid 412, and AMD. TLR3 is a protein that alerts the body’s immune system to infections.

The team assessed whether TLR3, Leu and Phe affected the viability of human retinal pigment epithelial (RPE) cells. They also used wild type and TLR3-knockout mice to evaluate the variants’ impact on apoptosis of RPE cells.

The team discovered (and used two independent case-control series to verify) that rs3775291 had a positive association with protection against dry AMD, although neither the Phe nor the Leu variant of TLR3 was correlated with wet AMD. The induced apoptosis in human retinal pigment epithelial cells with the Leu-Leu genotype was greater than in those with the Leu-Phe genotype, and was greater in the wild type mice than in the TLR3-knockout mice.

The researchers concluded that the Phe variant of TLR3 probably protects against dry AMD because it suppresses the death of RPE cells and that, since double-stranded RNA (dsRNA) is known to activate TLR3-mediated apoptosis, it is also probable that dsRNA may play a role in the development of dry AMD, which would indicate that short interfering RNA therapies may not be merely ineffective but possibly counter-productive in the treatment of dry AMD.