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GEN News Highlights : Nov 28, 2012
Epigenetics Implicated in Development of AMD
NIH scientists report that changes in how immune system genes function may result in age-related macular degeneration (AMD). The disorder is the leading cause of visual impairment in older adults.
"Our findings are epigenetic in nature, meaning that the underlying DNA is normal but gene expression has been modified, likely by environmental factors, in an adverse way," explained said Robert Nussenblatt, M.D., chief of the National Eye Institute’s (NEI) Laboratory of Immunology.
Environmental factors associated with AMD include smoking, diet, and aging. "This is the first epigenetic study revealing the molecular mechanisms for any eye disease," added Dr. Nussenblatt.
The study identified decreased levels of DNA methylation, a chemical reaction that switches off genes, on the interleukin-17 receptor C gene (IL17RC). The lack of DNA methylation led to increased gene activity and, in turn, increased levels of IL17RC proteins in patients with AMD. IL17RC is a protein that promotes immune responses to infections, such as fungal attacks.
The study, conducted by research teams from the NEI and other NIH institutes including the National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine; the University of Melbourne, Australia; and Oregon Health and Science University, appears in the Nov. 29 issue of Cell Reports.
"Our study also suggests IL17- and IL17RC-mediated immune responses can be crucial in causing AMD," added Lai Wei, M.D., Ph.D., also of NEI's immunology lab and first author on the paper. "By measuring IL17RC gene activity in at-risk patients, we have also potentially identified an early method to detect AMD."
AMD damages the light-sensitive cells of the macula, the central part of the retina that allows us to see fine visual detail. As the disease progresses, patients encounter great difficulty reading, driving, or performing hobbies and tasks that require hand-eye coordination. Treatments exist to prevent severe vision loss in certain types of advanced AMD but none prevent or cure the disease. Currently, two million Americans have advanced AMD and another seven million have intermediate stages.
In addition to AMD, changes in DNA methylation have been implicated in cancer, lupus, multiple sclerosis, and many other diseases. For example, researchers at the Duke-NUS Graduate Medical School in Singapore have identified numerous new subtypes of gastric cancer that are triggered by environmental factors. They published their findings last month in Science Translational Medicine.
"Gastric cancer is a heterogenous disease with individual patients often displaying markedly different responses to the same treatment," said Patrick Tan, M.D., Ph.D at Duke-NUS and lead author of the study. "Improving gastric cancer clinical outcomes will require molecular approaches capable of subdividing patients into biologically similar subgroups, and designing subtype-specific therapies for each group.”
Like many cancers, stomach cancer is caused by genetic mutations, but also by epigenetic alterations. In their study, Dr. Tan and colleagues used 240 primary tumors and cell lines to conduct the first full survey of the DNA methylation landscape (methylome) in gastric cancer. Their goal was to identify new molecular subgroups of gastric cancer not caused by primary genetic mutations, particularly those that might be targeted with therapies.
The researchers found that the gastric cancer methylome was widespread, with more than half of the CpG sites (specific locations along the DNA that are modified through the addition of a methyl group) analyzed demonstrating altered methylation patterns in cancer. Many of the methylation alterations were associated with significant changes in gene expression, suggesting that the methylation alterations may be functionally important in the development of gastric cancer.
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