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Gene Discovery Linked To Mysterious Chronic Food Allergy

"Study offers first molecular insight into eosinophilic esophagitis"

Friday, February 03, 2006

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 closely resemble illnesses such as acid reflux disease (also known 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, MD, PhD, 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 acid 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, PhD, 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, which had already been identified as a 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, MD, and Margaret H. Collins, MD, both of Cincinnati Children's) have shown that eosinophilic esophagitis affects one in 2,000 children in the Cincinnati region. Health care providers are beginning to see increased cases of eosinophilic esophagitis in many countries, such as England, Japan, Spain, Australia, Switzerland and Italy where more cases have been reported.

"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.

In terms of next steps, the identification of eotaxin-3 as a cause for eosinophilic esophagitis now places attention on the development of drugs that block this protein.

Computational Medicine

Dr. Rothenberg's study was done with the support of the Computational Medicine Center, a biomedical informatics research center focused on making fundamental discoveries into the origins and causes of pediatric and adult diseases and designing treatment that will make disease more preventable, illness more predictive and treatment more personalized. The center is a collaborative effort between Cincinnati Children's and the University of Cincinnati College of Medicine. It is funded with a $28 million grant from Ohio's Third Frontier Project.

The study was funded in part by the CURED Foundation (Campaign Urging Research for Eosinophilic Diseases); Burroughs Welcome Fund; the Buckeye Foundation; National Institutes of Health; and, the Food Allergy and Anaphylaxis Network.

-- Dr. Rothenberg is a leading scientist in the area of eosinophilic disorders. He has published extensively on molecular mechanisms of allergic responses, including an article in the New England Journal of Medicine, titled "Eosinophilia." He has earned numerous international awards, including the prestigious Pharmacia Allergy Research Foundation International Award for 1998.

-- Cincinnati Children's is a leading international referral center for eosinophilic disorders, with more than 300 patients. Physicians at Cincinnati Children's evaluate about three new patients each week.

-- The CURED Foundation was founded in 2003 by Ellyn and Fred Kodroff of Chicago. In 2003, their daughter, Jori, was diagnosed with an eosinophilic gastrointestinal disorder. The Kodroffs soon after launched CURED in order to raise public awareness and fuel research that would lead to new treatments for eosinophilic disease. CURED has raised in excess of $200,000 for research.

The rising concern about eosinophilic esophagitis has sparked interest from other affected families throughout the country who founded the American Partnership for Eosinophilic Disorders (APFED), an organization designed to support increased public awareness and research for eosinophilic disorders.

Cincinnati Children's is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health.