Yale scientist finds two genetic anomalies linked to macular degeneration

In late 2004, Josephine J. Hoh, Ph.D., associate professor of epidemiology and of ophthalmology and visual science, used new DNA chip technology to identify a gene for age-related macular degeneration (AMD). She found a single nucleotide polymorphism (SNP)—in this case a variant in the coding region of complement factor H (CFH) gene on chromosome 1—that is linked to an increased risk of developing both wet and dry forms of AMD.

Now, in findings published in the journal Science in October, Hoh has reported finding an independent SNP in a section of chromosome 10 that regulates the HTRA1 gene. The variant appears to increase the expression of the protein HTRA1 in the eyes of homozygotes, and people carrying two copies of the risk allele have a much higher risk of wet AMD.

“We found that patients with the HTRA1 SNP in both chromosomes were 10 times more likely to have wet AMD than those who have it in just one chromosome or no SNP,” said Hoh. “This may point to possible directions for effective treatment of wet AMD.”

AMD causes light-sensitive cells in the retina to break down, resulting in progressive loss of central vision. Of the two forms of AMD, the dry form is more common than the wet form. Wet macular degeneration can lead rapidly to blindness, while the dry form of AMD progresses more slowly.

The discovery marks the first time that a cross-ethnic approach was used to efficiently decipher a complex disease such as AMD. Hoh exploited differences in the progression of AMD in Caucasian and Chinese patients. In Caucasians, the proliferation of abnormal blood vessels is compounded by the development of large waste deposits called drusen. Chinese patients, she said, develop little or no drusen and progress directly to wet AMD.

Using DNA samples from Chinese patients with AMD, Hoh discovered the disease-causing variant in the control section of the HTRA1 gene. She then hypothesized that this same genetic variant causes wet AMD in Caucasians. “Finding a gold mine is very much easier if you have a good map showing where to dig. The discovery in the Hong Kong Chinese samples gave me the map,” she said. The confirmation of her hypothesis that the HTRA1 variant causes wet AMD in Caucasians was done in collaboration with Kang Zhang, M.D., Ph.D., of the University of Utah School of Medicine.

These studies demonstrate that each of these two major genes, CFH and HTRA1, affects the risk for a distinct component of the AMD phenotype: CFH influences the production of drusen associated with dry AMD, whereas HTRA1 influences blood vessel development, the hallmark of the wet disease type. When the two processes are combined, they lead to the composite characteristics seen in some cases of AMD.

“The marker variant we have identified in HTRA1 is very much associated with AMD, but function of the gene that causes wet AMD is unknown. We need to conduct further functional studies in order to understand the biological mechanisms,” said Hoh.