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Genetic Study Explains 74 Percent of Age-Related Macular Degeneration

Significant advance for understanding leading cause of blindness in elderly

March 6, 2006 - 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 they say affects more than 10 million people in the United States and is the most common cause of blindness in senior citizens.

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 on April 30. In that study it was found that AMD occurs when a common inherited gene variation is triggered, possibly by an infection. The gene is known as Factor H (See the report on this earlier study below this current report.)

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.

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.

Earlier Research Report

Variation in Gene That Regulates Immune Response Causes Age-Related Macular Degeneration When Triggered

Study suggests inflammation, other immune responses trigger genetic cause of blindness in elderly

April 30, 2005 – Age-related macular degeneration, the leading cause of blindness in the elderly, occurs when a common inherited gene variation is triggered, possibly by an infection, according to a new study led by researchers at Columbia University Medical Center and the University of Iowa, with an international research team.

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.  

The National Eye Institute estimates that there are 1.6 million people with AMD in the United States alone and that this prevalence will grow to 2.95 million by 2020.

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 study’s genetic analysis with patients and colleagues from the Harkness Eye Institute at Columbia University Medical Center and NewYork Presbyterian Hospital/Columbia, 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 College 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.

About Source:
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, medical education, and health care. The medical center trains future leaders in health care and includes the dedicated work of many physicians, scientists, nurses, dentists, and other health professionals at the College of Physicians & Surgeons, the School of Dental & Oral Surgery, 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. With a strong history of some of the most important advances and discoveries in health care, its researchers are leading the development of novel therapies and advances to address a wide range of health conditions.  www.cumc.columbia.edu

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