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Jonathan Haines, Ph.D.

Researchers identify eye disorder gene

BY: LEIGH MACMILLAN

3/11/2005 - Investigators at Vanderbilt University Medical Center and Duke University Medical Center have identified the first major gene that increases a person's risk of developing age-related macular degeneration (AMD).

AMD is a progressive eye condition that affects as many as 15 million people in the United States and is the leading cause of vision loss and legal blindness in people over age 60.

The researchers report this week in Science Express, the online version of the journal Science, that a common variant of the gene for Complement Factor H accounts for up to 43 percent of age-related macular degeneration.

The finding “opens the door toward the possibility of pre-symptomatic testing and potentially even pre-symptomatic treatment,” said first author Jonathan L. Haines, Ph.D., director of the Vanderbilt Center for Human Genetics Research. It also sheds light on the biological mechanisms underlying the disease and offers real hope for drug development, he said.

“Knowing this gene now narrows us from millions of potential targets for drug treatment and drug development to one. That's not bad,” Haines said.

Vision loss often occurs late in the progression of AMD, and current treatments help stabilize the disease but do not reverse its course, said Anita Agarwal, M.D., assistant professor at the Vanderbilt Eye Institute and study co-author. “Less than 2 percent of patients show improvement in vision with treatment when the center of the macula is involved by abnormal blood vessels,” she said.

“No one knows if available treatments — sometimes as simple as dietary changes — might prevent vision loss if they were given ten years earlier,” Haines said. “Now we potentially have a way of screening for patients at high risk and doing early intervention trials.”

The toll of AMD is expected to mount as the U.S. population ages, Agarwal said. The disease affects nearly 30 percent of people over age 75, she said. Severe AMD robs affected individuals of the sharp central vision necessary for everyday activities like reading, driving, watching television, safely navigating stairs, and identifying faces.

Although the underlying causes of AMD are unknown, risk factors include age, smoking, high blood pressure, exposure to harmful sunlight, obesity and diet. Genetics was also a known risk factor, although it was expected to be less important than the environmental factors, Haines said.

“No one expected the genetics to work out this way — that a single gene variant would potentially explain as much as 40 percent of a disease that affects millions of people,” Haines said.

Haines participated in an earlier multi-center effort that linked a DNA region on chromosome 1 to increased risk for AMD.

To find the gene, he and longtime collaborator Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics, and their teams examined DNA samples from two independent data sets.

One data set contained 182 families including members with and without AMD; the other set contained 495 patients with AMD and 185 individuals without the disease.

The investigators used modern genomic technologies and data from the Human Genome Project to zero in on the Complement Factor H (CFH) gene. A single variation in the CFH gene was strongly associated with AMD.

CFH participates in regulating inflammation; it puts the “brakes” on to protect cells from overactive inflammatory processes.

Chronic inflammation has been implicated in AMD, Haines said, but it is not known whether inflammation is a primary cause of the disease or a secondary mechanism.

The finding that a CFH variant accounts for such a large percentage of AMD “suggests that inflammation may be a more important aspect of the disease than had previously been appreciated,” he said. The researchers hypothesize that the CFH variant does not function appropriately to keep inflammation in check, leading ultimately to vascular damage and the abnormal growth of blood vessels characteristic of severe AMD.

Vanderbilt co-authors include Lana Olson, Kylee Spencer and Nathalie Schnetz-Boutaud.

The research was supported by the National Eye Institute, the National Institute on Aging and the National Center for Research Resources.

©2014 Vanderbilt University Medical Center
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