University of Iowa News Release
May 2, 2005
Study Adds Information Linking Gene To Blinding Disease
An international research team led by investigators at the University of Iowa and Columbia University Medical Center has found that inherited variations in the Factor H gene dramatically increase the likelihood of an older person developing age-related macular degeneration (AMD), the most frequent cause of irreversible blindness in developed countries.
The independent findings will appear the week of May 1 in the online edition of the Proceedings of the National Academy of Sciences. Three other independent studies on Factor H, which included some of the same results, were published in the March 10 online issue of Science magazine. The UI- and Columbia-led study was unique in several aspects, including its focus on the basic biological causes of AMD and making an important connection to a rare kidney disease.
The Factor H gene encodes a protein involved in controlling the body's first-line immune defense against bacterial and other infections. A better understanding of the gene can help scientists develop diagnostic and therapeutic tools.
The team was led by Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the UI Roy J. and Lucille A. Carver College of Medicine, and Rando Allikmets, Ph.D., the Acquavella Associate Professor in Ophthalmology and Pathology and Cell Biology at Columbia University College of Physicians and Surgeons, and included collaborators in the UI Departments of Ophthalmology and Otolaryngology; Columbia University Medical Center; the University of California, Santa Barbara (UCSB); Queen's University, Belfast; and the National Cancer Institute (NCI).
AMD causes central vision loss when drusen -- the common eye lesions that occur in people with AMD -- accumulate and damage the macula, a quarter-inch diameter region of the retina. No treatment currently exists for the early stages of the disease, which affects up to 50 million people worldwide. Treatment for advanced stages is limited.
In previous research, Hageman and current study authors Don Anderson, Ph.D., and Lincoln Johnson, Ph.D., of the UCSB Center for the Study of Macular Degeneration, implicated the complement cascade, the body's first line of immune defense, in drusen formation.
"Based upon those collective studies, we proposed that chronic local inflammation and activation of the immune system are responsible for drusen formation, which was later recognized clinically as AMD," Hageman said. "The results of the current study provide compelling evidence that this early prediction was correct."
The complement cascade normally recognizes and kills infectious invaders. However, the system sometimes mistakes healthy cells for foreign cells. When that happens, tissue damage and local inflammation can occur. To prevent this damage, proteins such as Factor H keep the system under tight control.
In the current study, Hageman's and Allikmets's team, along with geneticists at the NCI, led by Michael Dean, Ph.D., analyzed whether common genetic variants, called single nucleotide polymorphisms (SNPs), in the Factor H gene occur more often in individuals with AMD than those without the disease.
The results showed that a surprisingly large percentage of AMD patients inherit a specific pattern of SNPs in the Factor H gene, known as a haplotype, that make them more susceptible to AMD.
"We now understand the genetic variation that is behind age-related macular degeneration and are beginning to target the trigger that sets the process in motion," Allikmets said. "By targeting the molecules involved in inflammation and its regulation, we believe we can begin to develop therapies and diagnostic tools that could help countless people keep their sight."
Study co-authors Richard Smith, M.D., the Sterba Hearing Research Professor at the UI, and Giuliana Silvestri, M.D., at Queen's University, found that the same Factor H haplotype is present in 70 percent of individuals with a rare and oftentimes fatal kidney disease called membranoproliferative glomerulonephritis type II (MPGN II) or Dense Deposit Disease.
Individuals with MPGN II also develop ocular drusen, but at a much earlier age than in people with AMD. This commonality led the researchers to examine the role of the Factor H gene in AMD and MPGN II.
Smith said, "It is likely that individuals with AMD or MPGN II have a functional defect in Factor H protein that results in over-activation of the complement system or interferes with its ability to recognize foreign pathogens."
The scientists propose that this results in local tissue damage, particularly at vulnerable locations in the kidney and macula, which are similar in structure and function.
Anderson explained, "When we looked at the molecular composition of drusen years ago, we saw many of the constituent proteins were either part of the complement system or, like Factor H, involved in regulating it. That led us to the nearly inescapable conclusion that AMD, like many other age-related diseases such as Alzheimer's disease and atherosclerosis, involved a major inflammatory component.
"This conclusion was not met with universal enthusiasm by our colleagues," he added. "Now that the genetic evidence of Factor H involvement is in, it appears that the inflammation model of AMD is correct."
The investigators also showed that other haplotypes in the Factor H gene provide a degree of protection from acquiring AMD.
Researchers will further study the complement cascade to identify molecules that will be key to developing early diagnostic tests and treatments for AMD and MPGN II. They also will investigate the extent to which people with certain Factor H variants are likely to have other chronic, immune-related diseases.
"This kind of research 'takes a village,'" said study author Karen Gehrs, M.D., UI associate professor of ophthalmology and visual sciences. "Studying a disease as complex as AMD requires the collaboration of laboratory scientists and clinical practitioners, as well as study volunteers. It is very exciting to see it all come together to produce such a major finding in AMD."
The study was supported in part by grants from the National Eye Institute of the NIH, Research to Prevent Blindness Inc., Pfizer Inc., the American Macular Degeneration Foundation, the Milton and Ruth Steinbach Fund, the International Retina Research Foundation, and the Eye Research Institute, as well as unrestricted gifts to the UCSB Center for the Study of Macular Degeneration. Multiple eye banks, including the Iowa Lions Eye Bank, helped make the research possible through donated eye tissue.
"We are sincerely grateful to all the families that donated the eyes of their loved ones to the program and to all the patients, practitioners, colleagues, staff and volunteers who took time to participate in our studies," Hageman said. "Without their involvement, the study would not have been possible."
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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The following images are not copyrighted; however, please credit the National Eye Institute, NIH. Simulation of macular degeneration:
Diagrams of the eye, labeled and showing the retina and macula: http://www.nei.nih.gov/photo/eyean/index.asp -- reference NEA09 or NEA01