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Turning an eye blind
Researchers identify gene linked to the leading cause of age-related blindness
It takes a sharp eye to catch a single error in the 3 billion letter long genetic sequence of human DNA. But by using a combination of high-throughput biology and statistical genetics, researchers led by Rockefeller University’s Jürg Ott and colleagues at Yale University have spotted a tiny mutation that confers susceptibility to a highly prevalent form of blindness.
“We have shown that a variant, or polymorphism, of the complement factor H gene, which alters a protein whose normal function is to regulate the immune system’s attack of foreign invaders and abnormal cells, is involved in the development of age-related macular degeneration, the most common form of blindness in the United States for those over 60,” says Ott, professor and head of the Laboratory of Statistical Genetics at Rockefeller. “We believe this polymorphism is a strong risk factor for the disease.”
Age-related macular degeneration causes a loss of the central visual field necessary for detailed sight, reading, driving, sports participation and watching TV and movies. A characteristic of the disease is the build up of fatty deposits called drusen in the macula, the central region of the retina.
The gene variant identified by the researchers is known as a single nucleotide polymorphism (SNP), as it is derived from a single letter difference in the genetic sequence of DNA. Some of these differences may change a gene’s protein products in ways that may confer susceptibility to — or protection from — diseases. In this case, the complement factor H (CFH) SNP associated with age-related macular degeneration encodes for a different amino acid, as histidine substitutes for tyrosine at a specific position. The CFH gene lies in a region of human chromosome 1 that had been linked previously to age-related macular degeneration through family studies by other researchers.
Josephine Hoh, a former research assistant in Ott’s lab, now assistant professor in the division of chronic disease epidemiology at Yale’s School of Public Health, analyzed DNA taken from the blood samples of 146 unrelated patients, collected for the National Eye Institute-sponsored Age-Related Eye Disease Study (AREDS), designed to learn more about the natural history and risk factors of AMD and cataract and evaluate the effect of high doses of antioxidants and zinc on the progression of these conditions. She then compared the DNA from 96 patients with an advanced form of age-related macular degeneration with that from 50 healthy people who had little or no drusen deposits in their retinas.
The researchers genotyped more than 116,000 SNPs using the most advanced microarray technology and compared the frequency of each of them between the two groups of patients.
Then, under the supervision of Hoh and Ott, Ott lab member Robert Klein analyzed the data, and the CFH SNP was located.
Biochemical analysis of drusen by other researchers has shown that the deposits are largely composed of lipids, but also contain components of the immune system called complement. The complement system is a collection of related proteins that are the body’s front-line defense system — the innate system — that attacks foreign invaders while usually avoiding any attacks against healthy cells. One of the known properties of factor H is that it regulates the activation of complement components.
The researchers examined the eyes of four patients with age-related macular degeneration and found complement debris in the drusen, as well as in eye components called Bruch’s membrane and the intercapillary pillars. Other researchers also have detected complement components in the drusen of humans.
“The polymorphism produces a change in a specific amino acid in the complement factor H protein, which is located in the region that interacts with C-reactive protein and heparin,” says Hoh. C-reactive protein is associated with heart disease and high cholesterol levels and both C-reactive protein and heparin are associated with age-related macular degeneration.
The team reported their findings in the April 14 issue of Science, and say the work opens the door for new investigations of the role of genes in developing age-related macular degeneration, as well as suggesting possible treatments for the disease.

May 13, 2005



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