February 2010




Gene variant for POAG found

by Maxine Lipner Senior EyeWorld Contributing Editor


Study finds Barbados patients with gene variant at dramatically increased glaucoma risk

A newly discovered gene variant for primary open-angle glaucoma (POAG) found in the black population of Barbados could help point the way to a better understanding of the disease as well as effective new treatment options, according to Kang Zhang, M.D., Ph.D., director, Institute of Genetic Medicine, and professor of ophthalmology and human genetics, University of California, San Diego. The study, which was published in the Oct. 6, 2009, issue of the Proceedings of the National Academy of Sciences of the United States of America, has discovered a gene variant present in 40% of individuals with POAG in Barbados.

POAG is very common in the U.S. population. “It is somewhere around 3% to 5%,” Dr. Zhang said. “It is the leading cause of blindness in the African-American population.”

This problem is particularly pressing among those of African descent. “In blacks the prevalence of glaucoma is the highest of all the races, and in the Barbadian population it is even higher—double the amount,” Dr. Zhang said. “Eight percent to 10% of Barbadians have glaucoma.”

The study was an outgrowth of a broader investigation. “This was an extension of the Barbados Family Studies in glaucoma. The study surveyed the population in Barbados and determined that there is a high prevalence of glaucoma as well as high familial aggregation of glaucoma,” Dr. Zhang said. “All of this indicates that there’s a strong genetic predisposition for glaucoma in that population.”

Studying families

In the study, investigators performed linkage analyses in 146 families, drawing genetic samples from glaucoma patients, their spouses, and their children. Included here were 249 patients with glaucoma and 128 controls. Samples collected were compared with clinical records of glaucoma and the human genome was searched for a possible common gene. Results were extremely promising. Investigators found that they were able to make a ready connection. “We were able to identify a gene variant in chromosome 2 that was present in 40% of the glaucoma cases, whereas it was only present in 10% of the normal population,” Dr. Zhang said. “In the homozygote state, if a child inherits two copies, this variant gives an increased risk of developing glaucoma of 30-fold—a very dramatic increase.” For those with only one copy of the gene, there was only a four-fold increase in glaucoma occurrence.

Dr. Zhang sees the genetic significance here as profound. “To give an example of the scale of the relative risk of a patient having this variant: There have been about 10 genes identified for type 2 diabetes, all of which only give a six-fold increased chance of having the disease,” he said. “This one gene by itself is giving a 30-fold increased chance of having glaucoma.”

Dr. Zhang theorizes that the genetic connection was probably made many generations earlier. “Probably someone who came from Africa to this island had this mutation, and over the years the mutation expanded in the Barbadian population,” he said. “Because most of the patients in Barbados stayed there, the population was able to expand the gene pool and enrich the genetic mutations for this particular condition.”

While the gene itself has not yet been identified, investigators do know that it is located on the short arm of chromosome 2. “We don’t know the exact gene yet—we’re in the process of figuring that out now,” Dr. Zhang said. It is also unknown whether this mutation applies to other populations, such as African Americans. “All we know is that it’s a rich genetic risk for Barbados,” Dr. Zhang said. “But we do not know if this plays any role in the Caucasian or African-American populations.”

Future implications

Dr. Zhang sees the clinical implications here as two-fold. “The first implication is that we now have a marker that can be put into the screening process to identify people who are at a greater risk of developing glaucoma,” he said. “Right now it’s applicable in the Barbados population.”

The second implication of this new genetic link may be a broadening of the general understanding of primary open angle glaucoma. “We have some knowledge about the genes that are causing glaucoma,” Dr. Zhang said. “However, the vast majority of patients present with complex-free disease, and we really do not have much of a handle on what’s causing the condition.” Dr. Zhang believes that identifying the Barbados-linked gene will offer investigators some understanding of why this gene mutation is causing so many patients to develop glaucoma. “Hopefully we can develop a therapy based on this knowledge,” he said.

Dr. Zhang hopes that in the next year or two investigators will be able to identify the related genetic mutations, develop animal models, and then ultimately determine how to stave off damage due to glaucoma. “Genetic information in combination with stem cell therapy should be the next frontier to provide personalized medicine and therapy for glaucoma, where there’s currently no cure and no way to reverse vision loss,” he said.

Editors’ note: Dr. Zhang has financial interests with Acucela (Bothell, Wash.) and Genentech (South San Francisco, Calif.).

Contact information

Zhang: kangzhang@ucsd.edu

Gene variant for POAG found Gene variant for POAG found
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