Sunday, March 07, 2010
CINCINNATI – Pediatrics researchers have identified the first major gene location responsible for a severe, often painful type of food allergy that leaves its victims unable to eat a wide variety of foods. Eosinophilic esophagitis (EoE) also may cause weight loss, vomiting, heartburn and swallowing difficulties.
After performing a genome-wide association study, the study team found EoE was linked to a region of chromosome 5 that includes two genes. The likely culprit is the gene TSLP, which has higher activity levels in children with EoE compared to healthy subjects. In addition, TSLP has been previously linked to allergic inflammatory diseases, such as asthma and the skin inflammation atopic dermatitis.
The study appears online March 7 in Nature Genetics.
“This gene is a plausible candidate because of its biological role in allergic inflammation,” said study senior author Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. Hakonarson and colleagues collaborated with Marc E. Rothenberg, MD, PhD, director of the Center for Eosinophilic Disorders at the Cincinnati Children’s Hospital Medical Center.
Cincinnati Children’s provided the largest cohort of EoE patients used for the discovery phase of the study, according to Rothenberg. He said the study is an important step forward.
“This study indeed opens the door for deciphering the molecular basis of this growing enigmatic disease, ultimately allowing investigators to develop better treatment,” Rothenberg explained.
Only recently recognized as a distinct condition, EoE, like other allergies, has been increasing over the past 20 years. Based on pioneering research by Rothenberg and his team several years ago in Hamilton County, Ohio – where Cincinnati Children’s is located – EoE’s reported incidence is estimated to be at least one in 10,000 people. Its hallmark is swelling and inflammation in the esophagus, accompanied by high levels of immune cells called eosinophils. It can affect people of any age, but is more common among young men who have a history of other allergic diseases such as asthma and eczema. EoE is often first discovered in children with feeding difficulties and failure to thrive.
In the current study, the researchers performed a genome-wide analysis on 181 samples from the Cincinnati center, compared to nearly 2,000 healthy controls from The Children’s Hospital of Philadelphia (CHOP). They then replicated the initial findings with additional DNA samples from EoE patients at CHOP. The gene studies pointed to chromosome 5q22.1, which contains the TSLP gene. TLSP holds the genetic code to produce a cytokine, a specific signaling protein that regulates inflammatory responses occurring in allergic diseases.
Because children with EoE are often allergic to many foods, they may be limited to a special elemental formula or strict food-restriction diet containing limited food proteins to allow time for their symptoms to resolve. Physicians then perform tests to determine which foods a child can or cannot eat.
“Eosinophilic esophagitis is a highly allergic disease, and one that is rapidly expanding,” said allergist Jonathan M. Spergel, MD, a co-first author of the study, who sees large numbers of patients with EoE as director of the Center for Pediatric Eosinophilic Disorders at CHOP. “This is the first genome wide association study done on this disease, and now that we have elucidated a gene pathway, the hope is that physicians can eventually intervene in that pathway and discover a new treatment.”
Funding support for the Cincinnati Children’s portion of the study came from the National Institutes of Health, CURED (the Campaign Urging Research for Eosinophilic Disease), the Food Allergy Project and the Buckeye Foundation.
The Cincinnati Center for Eosinophilic Disorders (CCED) at Cincinnati Children's Hospital Medical Center is the international leader in caring for patients with these conditions and researching the cure. The center’s multidisciplinary team has extensive experience with these rare disorders and an intense interest in eosinophilic disorders, their effects on health, and the impact on individuals and families. For more information, please visit www.cchmc.org/cced.
Cincinnati Children’s Hospital Medical Center is one of 10 children’s hospitals in the United States to make the Honor Roll in U.S. News and World Reports 2009-10 America’s Best Children’s Hospitals issue. It is #1 ranked for digestive disorders and is also highly ranked for its expertise in respiratory diseases, cancer, neonatal care, heart care, neurology/neurosurgery, diabetes, orthopedics, kidney disorders and urology. One of the three largest children’s hospitals in the U.S., Cincinnati Children’s is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health.
President Barack Obama in June 2009 cited Cincinnati Children’s as an “island of excellence” in health care. For its achievements in transforming health care, Cincinnati Children’s is one of six U.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases. Additional information can be found at www.cincinnatichildrens.org.