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Gene discovery linked to increasingly diagnosed gastrointestinal disease

02.02.2006


Study offers first molecular insight into eosinophilic esophagitis



Researchers at Cincinnati Children’s Hospital Medical Center have discovered the first gene associated with eosinophilic esophagitis, one of a number of eosinophil-related diseases in which the body produces abnormally large amounts of white blood cells that can lead to allergy related illnesses. In eosinophilic esophagitis, the esophagus is overwhelmed with white blood cells and as a result patients of all ages develop symptoms that mimic illnesses such as gastroesophageal reflux disease, food allergies and inflammatory bowel disease.

The study, which is featured on the cover of the February 1 issue of the Journal of Clinical Investigation, explains the critical role of the gene, eotaxin-3, in disease.


"In this paper we uncover the first molecular insight into the disease by identifying a genetic program that distinguishes it from other forms of esophagitis (such as esophageal reflux)," according to Marc E. Rothenberg, M.D., Ph.D., the corresponding author of the study and director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s.

The genetic fingerprint in patients with eosinophilic esophagitis was compared to the fingerprint in control patients and patients with standard reflux disease. The researchers found a striking genetic signature for eosinophilic esophagitis. Even though eosinophilic esophagitis affects patients of all ages and is more common in males, the genes were similar regardless of gender, age and the allergic status of the patients. Importantly, they were completely distinct from the gene expressions in patients with reflux esophagitis.

Previous studies by Dr. Rothenberg and other Cincinnati Children’s collaborators across multiple disciplines have shown the rate of eosinophilic esophagitis has risen so dramatically in recent years that it may be more prevalent than other inflammatory gastrointestinal disorders, such as Crohn’s disease. But up until now, the pathogenesis of eosinophilic esophagitis has not been clearly understood.

The research study, led by the study’s first author Carine Blanchard, Ph.D., a research fellow in the Division of Allergy and Immunology at Cincinnati Children’s, examined the gene expression profile in the esophageal biopsies. Out of the entire human genome, containing approximately 30,000 genes, the gene that most correlated with eosinophilic esophagitis was eotaxin-3, an already known powerful eosinophil activating protein. This data, combined with analysis of the eotaxin-3 gene sequence in patients, strongly places the disease onus on eotaxin-3.

Patients with eosinophilic esophagitis usually show symptoms of chest and abdominal pain, dysphagia, heartburn, vomiting and food impaction (occurs when food gets stuck in the throat). It is diagnosed by a combination of testing, including skin allergy tests, but most importantly, it requires analysis of esophageal tissue specimens obtained by endoscopy.

Eosinophilic esophagitis is commonly treated by a combination of medications and a change in diet. Many patients are so allergic to food that they can no longer eat anything. As a result, they are fed a simple elemental diet through a feeding tube. It is a chronic illness, but with proper management, most patients lead functional lives.

Dr. Rothenberg and his team of physicians and researchers (including Philip E. Putnam, M.D., and Margaret H. Collins, M.D., both of Cincinnati Children’s) have shown that eosinophilic esophagitis affects one in 2,000 children in Hamilton County, Cincinnati. Health care providers are beginning to see cases of eosinophilic esophagitis in many countries, including England, Japan, Spain, Australia, Switzerland and Italy, and evidence is emerging that the incidence calculated by Dr. Rothenberg’s team is likely to hold true in these countries.

"It is hopeful that these findings will contribute to predicting the general outcome of eosinophilic esophagitis and building a molecular classification for diagnosis and therapy of esophagitis," Dr. Rothenberg said. The identification of eotaxin-3 as a cause for eosinophilic esophagitis now places attention on the development of drugs that block this protein.

Amy Reyes | EurekAlert!
Further information:
http://www.cchmc.org

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