Oct. 8, 2004 In a three-year analysis of more than 10,500 genes, one-third of the human genome, researchers at Johns Hopkins have found a starting point to establishing the genetic basis for sinus disease and the growth of nasal polyps, illnesses not well understood despite their prevalence. The findings, set for publication in the Journal of Allergy and Clinical Immunology online Oct. 8, could lead to development of targeted gene therapies or other treatments to control these conditions.
"This was a fishing expedition of sorts for sinusitis research, and a nontraditional approach from a scientific standpoint," said study lead author and otolaryngologist Jean Kim, M.D., Ph.D., assistant professor, The Johns Hopkins University School of Medicine. "The result was a host of very interesting leads as to which genes may play a role in controlling this illness and how we might prevent it in the future.
"There is no cure for chronic sinusitis and nasal polyps. The symptoms associated with this condition, such as facial pain and postnasal drip, are much more incapacitating to the patient than a common cold," added Kim. "One of the most common treatments is surgery to remove swollen tissue and nasal polyps, but soon after we cut them out, the polyps usually keep growing back and symptoms return. This also happens after treatment stops with other medications, such as oral or nasal steroids."
The National Health Interview Survey by the Centers for Disease Control estimated that approximately 15 percent of the American adult population suffers from sinusitis, the most common respiratory complaint in the United States. Nearly 20 percent of patients with chronic sinusitis develop nasal polyps. These conditions can have serious health consequences: swelling of the tissues within the sinus cavity which, in turn, results in the loss of sense of smell, slowing down of air circulation and drainage, causing mucous to build up, thus creating a breeding ground for infections.
Figuring out how these effects were related to the body's immune response was the objective of this study, one of the first studies to evaluate the genetic details of these two illnesses. As a first step, the researchers conducted a broad molecular analysis of both healthy and diseased sinus tissue from 14 patients. Using a "reverse genetics" methodology - in which no single gene is suspected in the hunt for causality - the researchers compared extracted RNA, a product of genes, from diseased tissue samples with RNA from normal tissue. The researchers then used a specially designed gene chip that allows for bulk testing of more than 10,000 genes, a robotic testing method called a microarray analysis, to determine if the increased actions or inactions of any particular genes stood out.
Of the genes studied, the researchers found that 192 were up-regulated, or present in increased amounts, while another 156 were down-regulated, or present in decreased amounts in the diseased tissue samples. In the diseased tissue, a gene was determined to be "up" if there was at least a twofold increase in its amount in samples tested, and a gene was "down" if it had at least a 50 percent decrease in amount.
The researchers then narrowed their initial focus to the top-four "up" genes and the most common "down" gene to see if any proteins, as the products of genes, were also present in significantly larger or smaller amounts than normal. Changes in proteins and genes can be clues to a genetic basis or origin of a disease. This may subsequently lead to the development of new therapy for a condition (by controlling the actions of the protein).
Three of the four "up" genes, including two proteins known to have antibacterial activity, had their increased amounts confirmed by specific mRNA and protein analysis. Actual increases in the amounts of the fourth gene could not be validated.
Further analysis confirmed that one particular protein, called CC10, was present in severely depleted quantities as the single-most down-regulated gene. CC10 is a protein, found primarily in the airways of the lung, among other organs. This protein is thought to be a potent anti-inflammatory molecule and plays an important role in the immune response. While its precise biochemical and molecular functions are unknown, CC10 is used as a treatment for underdeveloped lungs in premature babies, where it suppresses inflammation.
"We were particularly surprised and excited to find low levels of this protein CC10," said senior author Bruce Bochner, M.D., professor of medicine and director of Hopkins' Division of Allergy and Clinical Immunology. "This protein is usually increased by steroid therapy, yet it was extremely low in all of our study subjects despite their use of steroid sprays into the nose. So, it raises the possibility of one day treating these defects with a nasal spray that is specific to raising levels of CC10."
"This study lays the initial groundwork for additional studies on what has been up until now a poorly understood and confounding illness," said Kim. "We now have many lead candidate genes which may play a role in causing sinus disease. These studies may lead to new treatments for patients with chronic rhinosinusitis and nasal polyps."
The study, which ran from March 2000 to March 2004, was funded by the National Institutes of Health.
Another Hopkins investigator in this research was Zheng Lui, M.D. Microarray analysis was performed at the lab facilities of Wyeth Discovery Research, Metabolic & Respiratory Diseases, Cambridge, Mass., by Joseph Sypek, Ph.D. and I-Ming Wang, Ph.D. Additional assistance was provided by Frank Oppenheim, D.M.D., Ph.D., Department of Peridontology and Oral Biology, Boston University School of Medicine, Boston, Mass.
Sinusitis is a prevalent and costly disease, with annual U.S. health care expenditures of nearly $6 billion, according to the U.S. government's Agency for Health Care Research and Quality. Every year, sufferers make more than 18 million office visits to the family doctor and each misses on average four days of work. Sinusitis rates are relatively high in the Midwest and South compared with the Northeast and Western regions of the country.
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