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r. Rando Allikmets, assistant professor of ophthalmic science (in ophthalmology and pathology) and the Louis V. Gerstner Jr. scholar in ophthalmology, is putting more than $1 million worth of grants into finding and studying genes involved in age-related macular degeneration, the leading cause of vision loss in the elderly.



Age-related macular degeneration is an eye disease in which the macula, the central part of the retina, deteriorates and dies, causing central vision loss and making driving and reading impossible. The "dry" form of the disease typically develops after cellular debris collects under the macula. In the "wet" type, abnormal blood vessels form and leak under the retina, which causes a scar to form and destroys central vision. There is no cure and current treatments are largely ineffective.

For people over age 75, about 30 percent—10 million—are affected by the disease to some extent. Of those, 2 million have severe vision loss in at least one eye, which happens at the end stage, Dr. Allikmets says. The disease is becoming more prevalent as the population ages.

Getting at the genetic causes of the disease will not be easy. The adult forms of macular degeneration are complicated because they involve many genes and no one knows much about the specific role individual genes play in this disorder.

However, what is known already is proving helpful. In 1997, Dr. Allikmets was the first to identify the gene for Stargardt disease, one of the more prevalent forms of juvenile macular degeneration. During his past two years at Columbia, Dr. Allikmets has been applying what he learned from the juvenile forms to the adult disease. He has shown that mutations in the gene that causes Stargardt disease, called the adenosine triphosphate-binding cassette transporter retina (ABCR) gene, are also associated with age-related macular degeneration.

People with a mutation in one copy of ABCR are more susceptible—three to five times more susceptible—to developing the adult version of macular degeneration. If both ABCR genes are mutated, an individual develops Stargardt disease. Recent studies, including those by Dr. Allikmets, have estimated that in the Western world about 10 percent of all age-related macular degeneration cases involve this gene. More than 400 mutations have been identified in this gene, with some more prevalent in Stargardt and some seemingly associated with macular degeneration.

Another gene implicated in the adult disease is apolipoprotein E (ApoE). ApoE has an allele, the epsilon 4 allele, that protects a person from developing the illness but makes people more susceptible to Alzheimer's disease.

Armed with this information, Dr. Allikmets has designed a study funded by two grants from the National Institutes of Health's Eye Institute—one for $700,000 over three years to support the research and the other, a supplemental, one-time $350,000, to purchase equipment to do the study.

Dr. Allikmets will be applying association analysis to find other genes implicated in macular degeneration. Association analysis involves matching large cohorts of people who have macular degeneration with healthy people or controls by ethnicity and age to determine which genetic variants are prevalent in patients.

First, he is picking candidate genes using gene expression microarray technology to see which are expressed in the retina and combining that with what is known about eye genetics. Dr. Allikmets plans to collaborate with researchers from and use the gene expression microarray facilities at the Institute for Cancer Genetics, the Naomi Berrie Diabetes Center, and the Columbia Genome Center. "There is no foolproof criteria for finding candidate genes," Dr. Allikmets says. "You use all available knowledge and with some visionary ideas and a bit of luck your picks should be good."

Once the candidate genes are identified, genetic differences between patients and controls will be uncovered by looking at single-nucleotide polymorphisms or SNPs (pronounced "snips") in the DNA in each study participant's blood sample. A SNP represents a change in one base pair of DNA at a particular position within a gene. Dr. Allikmets plans to put 1,000 SNPs—10 SNPs from 100 candidate genes in the eye—on one genotyping microarray chip. That chip will be used to screen the blood samples to assess which SNPs are more prevalent in the patients. Dr. Allikmets will use genotyping microarray chips and scanners designed by Asper Biotech, a company based in Tartu, located in Dr. Allikmets' native country of Estonia. In addition, he has installed high-pressure liquid chromatography equipment for mutation detection.

So far, Dr. Allikmets has received blood samples from about 1,000 study participants. He plans to get blood samples from 2,000 patients and 2,000 controls over the next three years. To reach that goal, Dr. Allikmets is working with Dr. Theodore Smith, associate clinical professor of ophthalmology, and Dr. Gaetano Barile, assistant professor of clinical ophthalmology, and with doctors at New York area hospitals.

Participants must fill out a standard questionnaire about their ethnic origin and environmental factors because ethnicity, gender, smoking, and high blood pressure, for example, are important variables in the study. Women, smokers, and people with hypertension may be more susceptible to the disease.

"We are looking for more people to join the trial," Dr. Allikmets says. "It's going to be a challenge to find the genes, but when we do, hopefully it will help in diagnosing and treating the disease."

For more information about participating in the macular degeneration trial, please visit the Columbia macular degeneration study web site at
http://www.amdgenetics.hs.columbia.edu/

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