Genetics of Eosinophilic Esophagitis.

摘要

Eosinophilic esophagitis (EE) is an emerging worldwide food allergic disorder associated with polysensitization to multiple food allergens, resulting in greatly restricted diets and chronic gastroesophageal reflux disease-like symptoms in many individuals. EE has a strong genetic component based on the frequent presence of a familial inheritance pattern, the high sibling risk ratio (approximately 80-fold) and the demonstration that a single nucleotide polymorphism (SNP) in the eotaxin-3 gene confers disease susceptibility. In order to dissect disease pathogenesis in humans, we are now taking genetic approaches based on genome-wide expression profile analysis of esophageal tissue, as well as a genomic analysis based on a candidate gene approach. The central hypothesis of our grant is that EE has strong genetic components that can be elucidated by a candidate gene approach focused on genes involved in asthma, allergy, and celiac disease. Using this approach, our preliminary studies have led us to hypothesize that EE susceptibility involves the IL-2/IL- 21 genetic locus, a region known to be involved in immune-mediated diseases, especially autoimmunity. We have been pursuing candidate gene validation (Aim 1) and biological assessment of one lead candidate, IL-21 (Aim 2). We have identified preliminary genetic susceptibility loci involved in EE, which has led us to the identification of key potential pathogenic steps involving TSLP, IL21, and TGFb.