Researchers at Duke University Medical Center and Vanderbilt University Medical Center have pinpointed the first major
gene that determines an individual’s risk for developing age-related macular degeneration (AMD). The chronic, progressive
disease — which affects as many as 15 million people in the United States — is the leading cause of visual impairment and
legal blindness in the elderly.
A common variant of the gene, called complement factor H (CFH), explains approximately 43 percent of the risk of AMD among
older adults, the researchers estimated. The team identified the disease-related gene after screening 182 families affected
by AMD and 495 other individuals with the condition.
The researchers will report their findings in a forthcoming issue of Science (published online March 10, 2005, in Science Express).
The genetic advance sheds light on the mechanisms underlying the disease and could lead to new avenues for treatment, the
researchers said. The finding might also yield methods for identifying those patients at the greatest risk for developing the
condition before symptoms arise, when therapies and changes in lifestyle might be most effective in slowing the disease
“Macular degeneration is an important cause of blindness and loss of independence in the elderly,” said Margaret
Pericak-Vance, Ph.D., director of the Duke Center for
Human Genetics and senior author of the report. “This gene opens the door to a whole new understanding of the factors
that contribute to this disease.
“The finding may ultimately lead to new methods for identifying those at high risk for macular degeneration and suggests new
pathways for drug development,” she added.
AMD causes progressive impairment of central vision, and is the most common cause of legal blindness in Americans over the
age of 55. The disease causes damage to the retina, a thin layer of nervous tissue that lines the inside of the eye. The
primary site of damage occurs in the central retina, a portion called the macula.
The retina functions like film in a camera, explained ophthalmologist Eric Postel, M.D., of the Duke University Eye Center. Without proper retinal function, images
cannot be captured and sent to the brain. The macula is critical for fine, detailed vision. In patients with severe AMD,
progressive blurring and loss of central vision due to damage of the macula may leave people unable to perform everyday
activities such as driving, reading, writing checks and recognizing faces, he said.
“Fifteen million people in the United States have AMD and 1.5 million have the most severe form,” said Postel, the head
clinician on the study. “By the year 2030, as the baby boomer generation ages, the number of people with AMD is expected to
AMD exists in two forms: the “dry” form and more severe “wet” form. In the dry form, degeneration of the macula can cause
slow, progressive vision loss over the course of months to years. While there is no cure, vitamin supplements have been shown
to slow the disease in some individuals with this milder form.
In ten percent of patients, the disease progresses to the wet form in which abnormal blood vessels under the macula leak
blood and fluid causing rapid damage and a precipitous loss of vision. Patients with wet AMD can receive several treatments
to prevent further vision loss — including laser surgery and recently approved injections of a drug into the eye.
However, available therapies usually can only stall the disease progression, Postel said. None effectively reverse the course
of the disease.
While the underlying causes of AMD had remained largely unknown, risk factors include age, smoking, high blood pressure,
obesity and diet, said Pericak-Vance. In addition to such environmental factors, evidence from family and twin studies had
indicated a significant genetic contribution to the disease, she added.
Earlier studies by the Duke and Vanderbilt teams and others had linked AMD risk to a particular region on chromosome 1. To
identify the gene responsible, the researchers examined two independent data sets: the first contained 182 families including
members with and without AMD and the second contained 495 individuals with AMD and 185 unrelated individuals not affected by
The researchers zeroed in on a smaller region of chromosome 1 with a strong association to the disease in both data sets.
Further DNA sequencing of the CFH gene that is within that region revealed that individuals with one or more copies of a
particular gene variant were more likely to have AMD compared to those with other versions of the gene, they reported. When
the researchers restricted the analysis to individuals with the more severe, wet form of AMD, the association between the
gene variant and the disease became even stronger.
The researchers estimated that the CFH variant may be responsible for up to 43 percent of all cases of AMD.
Earlier studies had suggested that CFH may play a role in protecting blood vessels from inflammation and damage, a function
which might explain its role in AMD, the researchers said.
“We knew that chronic inflammation played a role in macular degeneration, but we didn’t know if that was a primary cause of
the disease or a secondary symptom,” said Jonathan Haines, Ph.D., of Vanderbilt Center for Human Genetics Research and first
author on the report. “The finding that complement factor H is an important contributor to the disease suggests that
inflammation may be a more important aspect of the disease than had previously been appreciated.”
Given that the gene plays such a large role in AMD, further studies of CFH and the cellular components with which it
interacts might lead to a rapid increase in understanding of the biology of the disease, the researchers added. That
information, in turn, should allow scientists to advance on new treatments and preventive therapies.
Collaborators on the study include Michael Hauser, Silke Schmidt, William Scott, Paul Gallins, Shu Ying Kwan, Maher
Noureddine and John Gilbert, of the Duke Center for Human Genetics; Lana Olson, Kylee Spencer, Nathalie Schnetz-Boutaud and
Anita Agarwal, of the Vanderbilt University Medical Center. The National Eye Institute supported the work. Additional
resources came from the National Institute on Aging and the National Center for Research Resources to Vanderbilt University.
Contact: Kendall Morgan
Duke University Medical Center