The gene, known as Factor H, encodes a protein that regulates immune defense against infection caused by bacteria and viruses. People who have an inherited variation in this gene are less able to control inflammation caused by these infections, which may spark age-related macular degeneration (AMD) later in life, the study finds.
Published in this week's Proceedings of the National Academy of Sciences, the results suggest that targeting the molecules involved in immune system response may provide powerful new therapies for treating and preventing 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," said Rando Allikmets, Ph.D., Acquavella Associate Professor in the department of ophthalmology and the department of pathology & cell biology at Columbia University College of Physicians and Surgeons. "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."
Potential therapies could involve delivering healthy Factor H directly to the eye to short-circuit the disease process; extracting stem cells from the eye so they could be reengineered and re-implanted; or partial transplantation of the liver - the body's main source for Factor H.
Other research has recently established the link between the Factor H gene and AMD by scanning the human genome for variations in gene sequences, but this new research is the first to examine the roots of AMD from a biological perspective and to explore the role that immune response plays in triggering the disease.
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.
The study was conducted in two parts - biology and genetics. Dr. Allikmets, senior author on the paper, led the genetic analysis in the study, in collaboration with principal investigator Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa Roy J. and Lucille A. Carver School of Medicine, who conducted the biological research. An international team of researchers was engaged in the project including scientists at the National Cancer Institute, the National Institutes of Health (NIH), the University of California at Santa Barbara (UCSB), and Queens University, Belfast, United Kingdom.
Dr. Allikmets began his career focusing on a different disease - cancer. As an investigator for the National Cancer Institute, in 1997 Allikmets discovered the ABCR gene (also known as ABCA4), as the first gene involved in a substantial, but small fraction of age-related macular degeneration. This discovery set him on the path of pursuing research in the area of AMD genetics, and he joined Columbia University Medical Center in 1999 to pursue this groundbreaking research.
The researchers examined 900 AMD patients and 400 healthy controls and noticed that half of all AMD patients have an inherited pattern of genetic variants in the Factor H gene - known as a haplotype - that make them more susceptible to AMD. Different haplotypes in the Factor H gene in about one third of the population provide varied degrees of protection from acquiring AMD.
The Iowa team also examined a large collection of donated eye samples and observed that the activation of the immune system results in the formation of drusen - pockets of inflammation that are the precursors to AMD.
The new findings link variations on the Factor H gene - which was found to be accumulated in drusen - directly to the process leading to AMD. The study found that compared to control subjects, patients with AMD were more likely to have single nucleotide polymorphisms that weaken the ability of Factor H to inhibit the immune response - known as the alternative complement cascade - thus making them more susceptible to inflammation and the disease.
While it would seem that "anti-inflammatory" drugs could mitigate the inflammatory onslaught, the researchers say most do not work on this leg of the complement system.
The genetic pre-disposition to AMD exists in approximately half of the Caucasian population. But not everyone who has this genetic variant gets AMD, so what causes this mechanism to activate?
"We believe inflammation from infections might kick start the process that leads to AMD," said Dr. Hageman. "The variation in Factor H strengthens the immune response, keeping infections under control early, but ironically that may contribute to a chronic disease like AMD later in life." The Columbia and Iowa scientists were able to make this connection in large measure by studying a rare form of kidney disease called MPGN II. Patients with this condition often share the same kind of eye lesions as individuals with AMD. And, in fact, a genetic determinant of the two diseases had been previously linked to the same chromosome - chromosome 1. Thus, Factor H was thought to be a prime suspect in both diseases.
"It has been always assumed that AMD must have environmental triggers that turn on or aid the pathological process. Our research suggests that the trigger is a specific inducer of the alternative complement pathway, such as an infection, systemic disease, a vaccination, or another unusual agent. Interestingly, countries where the vaccination rate is highest also experience an elevated rate of AMD," said Dr. Allikmets.
The researchers continue to conduct new studies based on their results to further understand the triggers for this gene.
"This is an area for epidemiologists to study, but as our research progresses we should eventually be in a position to suggest treatment that could keep many people from going blind," he said.
The research was supported by the National Institutes of Health, American Macular Degeneration Foundation, International Retina Research Foundation, Eye Research Institute, Pfizer, Foundation Fighting Blindness, Ruth and Milton Steinbach Fund, and Research to Prevent Blindness, Inc.
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