Gene identified that confers susceptibility to age-related macular degeneration

By combining the tools of high-throughput biology and statistical genetics, scientists at Rockefeller University, Yale University School of Public Health and the National Eye Institute have identified a gene that confers susceptibility to age-related macular degeneration (AMD), the most common cause of vision loss in the United Sates for those over 60.

Reported in the March 10 issue of Science Express, the finding opens the door for new investigations of the role of genes in developing AMD and possible treatments for this disease.

"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 AMD," says senior co-author Jürg Ott, Ph.D., professor and head of the Laboratory of Statistical Genetics at Rockefeller. "We believe this polymorphism is a strong risk factor for the disease."

The gene variant, known as a single nucleotide polymorphism (SNP), derives 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 AMD 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 AMD through family studies by other researchers.

The research team was led by senior co-author Josephine Hoh, Ph.D., an assistant professor in the Division of Chronic Disease Epidemiology at Yale's School of Public Health. Before joining Yale in 2003, Hoh was a research assistant professor in Ott's lab.

For the research reported in Science Express, Hoh used DNA taken from blood samples collected for the National Eye Institute-sponsored Age-Related Eye Disease Study (AREDS). The AREDS was 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.

AMD is the leading cause of blindness in the developed world, and most sufferers are older than 60. It causes a loss of the central visual field necessary for detailed sight, reading, driving, sports participation and watching TV and movies. A characteristic of AMD (both the "dry" and wet forms) is the build up of fatty deposits called drusen in the macula, the central region of the retina.

Hoh and colleagues analyzed DNA from 96 unrelated patients with an advanced form of AMD and 50 healthy people who had little or no drusen deposits in their retinas.

The controls were chosen to be older than those with AMD. The study was carefully designed by matching other potential factors such as ethnicity, gender and smoking to ensure the only differences between the two study groups was disease status and genetic background

The researchers genotyped more than 116,000 SNPs using the most advanced microarray technology and compared the frequency of each of the 116,000 SNPs in the two groups, patients and controls.

Under the superevision of Hoh and Ott, Ott lab member Robert Klein, Ph.D., the first author of the paper, played a major role during course of the project, which include genotyping and analyzing the data generated by the microarray.

"Robert's unique background of molecular and computation biology was crucial to the success of this project," says Hoh.

Biochemical analysis of drusen by other researchers has shown that the deposits are largely composed of lipids, but a small portion of the drusen are 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, the "self." And 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 AMD 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 AMD.