University of Iowa News Release
March 6, 2006
Genetic Finding Explains 74 % Of Age-Related Macular Degeneration Cases
A new study led by Columbia University in collaboration with the University of Iowa and the National Cancer Institute pinpoints the role that two genes -- Factor H and Factor B -- play in nearly three out of four cases of age-related macular degeneration (AMD).
The findings indicate that 74 percent of AMD patients carry certain variants in one or both genes that significantly increase their risk of this devastating eye disease that affects more than 10 million people in the United States.
The study, which appears in the March 5 online issue of Nature Genetics, provides targets for developing therapeutic interventions. The research is a continuation of work published last year by the same teams in the April 2005 issue of the Proceedings of the National Academy of Sciences (PNAS).
The latest Nature Genetics findings were led by Rando Allikmets, Ph.D., the Acquavella Associate Professor in Ophthalmology, Pathology and Cell Biology at Columbia University Medical Center, with collaborating groups headed by Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences in the UI Roy J. and Lucille A. Carver College of Medicine, and by Michael Dean, Ph.D., at the National Cancer Institute of the National Institutes of Health.
"These findings are exciting because they solidly point to the roles of the Factor H and Factor B genes, and thus, the central role of a specific immune response pathway -- known as the alternative complement pathway -- in the development of AMD," Hageman said.
The earlier study showed that several variants in the Factor H gene significantly increase the risk of developing AMD. Factor H encodes a protein that helps control the alternative complement pathway, which is an important branch of the immune system.
Normally, the protein works to shut down an immune response -- inflammation -- against bacterial or viral infection after the infection is eliminated. However, people with the inherited risk-increasing variations of Factor H are less able to control inflammation caused by bacteria, viruses or as yet unidentified triggers, which may spark AMD later in life.
The investigators examined additional genes found in the same immune response, or complement, pathway that contains Factor H for their potential role in the development of AMD.
The genetic analysis of 1,300 people identified Factor B as the major modifier of the disease. The discovery makes good biological sense: while Factor H inhibits the immune response to infection (inflammation), Factor B activates the same response. Because of these complementary roles, a protective Factor B variation can protect against AMD, even if one carries a risk-increasing variant of Factor H, and vice versa.
As described in Nature Genetics, the two genes explained nearly three out of four AMD cases: 74 percent of the subjects with AMD had either the Factor H or Factor B risk variant (or both), but no protective variants of either gene.
"I am not aware of any other complex disorder where nearly 75 percent of genetic causality has been identified," said Allikmets, who is senior author of the paper. "The study confirms the association not just statistically and genetically but, most important, pinpoints the biological origin of the disease."
The findings give the teams clearer research targets for developing therapeutic interventions. Currently, no cure exists for AMD. Researchers at the UI and Columbia University will now search for specific viral and bacterial culprits.
"Although the new findings explain much of the genetic risk, the specific triggers that set off the immune response and subsequent inflammation are still unknown," Hageman said.
"It is my sincere pleasure to work with this talented team and to be involved in these important studies that identify the genetic basis for the role of the complement system, which we earlier identified, in this truly devastating disease," Hageman added.
More than 50 million people worldwide are estimated to have irreversible blindness as a result of macular degeneration, making it the most common cause of blindness for those over 60. An estimated 30 percent of the population will have some form of AMD by the time they reach age 75. The disease is marked by a progressive loss of central vision due to degeneration of the macula, which is the region of the retina responsible for fine, central vision.
The research was supported by the National Institutes of Health, the Widgeon Point Charitable Foundation, the Wallach Foundation, the Elyachar Foundation, the Kaplen Foundation, the International Retina Research Foundation, the Macula Foundation, Inc., the Foundation Fighting Blindness, the Ruth and Milton Steinbach Fund, and Research to Prevent Blindness, Inc.
For information about the research published in 2005 in PNAS, see this University of Iowa news release: http://news-releases.uiowa.edu/2005/may/050205amd_study.html.
University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at www.uihealthcare.com.
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NOTE TO EDITORS: This release was adapted from a news release provided by Columbia University Medical School.