New genetic discovery explains 74 percent cases of age-related macular degeneration

Significant advance for understanding leading cause of blindness in elderly

A new study, led by researchers at Columbia University Medical Center, pinpoints the role that two genes – Factor H and Factor B – play in the development of nearly three out of four cases of age-related macular degeneration (AMD), a devastating eye disease that affects more than 10 million people in the United States.

Findings indicate that 74 percent of AMD patients carry certain variants in one or both genes that significantly increase their risk of this disease.

Published in Nature Genetics, the research is a continuation of work published last year by the same team in the Proceedings of the National Academy of Sciences (PNAS, April 30, 2005 issue, see Columbia press release: http://www.cumc.columbia.edu/news/press_releases/AMD-Allikmets.html). Led by Rando Allikmets, Ph.D., the Acquavella Associate Professor in Ophthalmology, Pathology and Cell Biology at Columbia University Medical Center, the research team included collaborating groups headed respectively by Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa 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.

The PNAS study showed that several variants in the Factor H gene significantly increase the risk of developing AMD. Factor H encodes a protein that helps shut down an immune response against bacterial or viral infection, once the infection is eliminated. People with these inherited risk-increasing variations of Factor H are less able to control inflammation caused by infectious triggers, which may spark AMD later in life.

Though the effect of Factor H on AMD is large, variation in this gene alone does not fully explain who gets AMD and who doesn't. As described in the PNAS paper, about one-third (29 percent) of people with a Factor H risk variant had not been diagnosed with AMD.

The investigators decided to look for additional culprits and focused on genes in the same immune response pathway that contains Factor H.

Their genetic analysis of 1,300 people quickly identified Factor B as the major modifier of the disease. The discovery makes good biological sense: while Factor H is an inhibitor of the immune response to infection, Factor B is an activator. Because of the complementary roles of the these two genes, 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 Dr. Rando Allikmets, who is senior author of the paper.

"These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of AMD. We confirmed this association not just statistically and genetically but, most importantly, pinpointed the biological origin of the disease," added Dr. Allikmets. "In just a few short years, we've gone from knowing very little about what causes AMD to knowing quite a lot. We now have clear targets for early therapeutic intervention."

Though the new paper explains much of the genetic risk, the specific triggers that set off the immune response and subsequent inflammation are still unknown. Researchers at Columbia University Medical Center and the University of Iowa are now searching for specific viral and bacterial culprits.

"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 – a pathway that my colleagues and I identified a number of years ago – in this truly devastating disease," said Dr. Hageman.

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. It's estimated that 30 percent of the population will have some form of AMD by the time they reach the age of seventy-five. The disease is marked by a progressive loss of central vision due to degeneration of the macula--a region of the retina and the area responsible for fine, central vision.

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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.

Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders in health care and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center researchers are leading the discovery of novel therapies and advances to address a wide range of health conditions. www.cumc.columbia.edu

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