Researchers have discovered a gene linked to age-related maculopathy

University of Pittsburgh researchers have discovered a gene linked to age-related maculopathy (ARM), the leading cause of untreatable blindness in the elderly. Their discovery suggests a simple test might be able to identify those at risk for what is commonly known as macular degeneration (AMD) and may lead to the development of more effective preventive strategies.

Researchers report that variations of a gene called PLEKHA1 are strongly associated with a person's risk of developing ARM. The results, a culmination of 15 years of research, will be published in the September issue of the American Journal of Human Genetics and are currently available online.

The discovery of the gene came about through the team's efforts to map the genes of 612 families affected by ARM and an additional 323 individuals without a history of macular degeneration. Pooling data from a number of gene mapping studies, researchers were able to identify multiple locations on the chromosomes where there are common gene variants among people with ARM. Specifically, researchers found that a region on one of these chromosomes, chromosome 10, was the one most likely to contain a major gene that influences the risk of ARM. Further analysis of chromosome 10 found that a variation in PLEKHA1 to be strongly associated with a person's risk of developing ARM.

Earlier this year, researchers from Rockefeller University, Yale University, The National Eye Institute, Duke University, Vanderbilt University, University of Texas Southwestern, and Boston University used similar methods to identify the first gene variant thought to be a major contributor to ARM, complement factor H (CFH) on chromosome 1. The Pittsburgh study confirms involvement of this gene and, for the first time, shows that the association results also accounted for findings from previous genetic studies of AMD families. Importantly, the new study found that having both CFH and PLEKHA1 indicate a greater risk for macular degeneration.

"CFH was the first piece of the puzzle," said Michael Gorin, M.D., Ph.D., professor of ophthalmology, University of Pittsburgh School of Medicine, and professor of human genetics, University of Pittsburgh Graduate School of Public Health. "To fully understand the pathology of macular degeneration, we knew we needed to expand our investigation to find all of the genes that play a part in this condition. PLEKHA1 is an important second piece, and we'll keep searching for the rest of the pieces until we get this solved."

By identifying a number of genetic variants for ARM, researchers hope to use this information to develop a simple set of DNA tests to identify individuals who are at increased risk of this sight-robbing condition. Additionally, they hope to develop new preventive strategies and a better understanding of how ARM occurs.

An important clue to understanding the cause and mechanism of ARM was revealed through this discovery. PLEKHA1, like CFH, is involved in the cellular processes related to inflammation, which supports the hypothesis that damage caused by ARM is, in part, due to inflammation.

ARM is the leading cause of untreatable blindness in the elderly and despite recent advances in the treatment of some forms of this condition, it continues to be a serious threat to vision with no known cure. An estimated 200,000 Americans develop a severe form of AMD each year, making it the leading cause of blindness in people aged 65 and older. As many as 30 percent of individuals over the age of 75 have evidence of macular degenerative changes.

In addition to Dr. Gorin, contributing authors to this study are Johanna Jakobsdottir, graduate student in the department of biostatistics, Graduate School of Public Health (GSPH); Tammy Mah, department of ophthalmology, School of Medicine; Daniel Weeks, Ph.D., professor in the departments of human genetics and biostatistics, GSPH; Robert Ferrell, Ph.D., professor in the department of human genetics, GSPH; and Yvette Conley, Ph.D., assistant professor in the department of health promotion and development, School of Nursing, and assistant professor in the department of human genetics, GSPH.

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