Identification of a Genetic-Molecular Linkage for EoE Opens New Doors for Treatment

A gene called CAPN14 has been identified as a novel genetic component in epithelial tissue in the esophagus, and the gene’s interaction with the immune hormones thymic stromal lymphopoietin (TSLP) and interleukin 13 (IL-13) may explain why some patients develop eosinophilic esophagitis (EoE), a hard-to-treat food allergy marked by chronic inflammation of the esophagus.

In effect, EoE turns out to develop from interplay of a patient’s underlying genetic susceptibility to allergies and a tissue-specific process dictated by the molecular aspects of the CAPN14 gene, according to Marc Rothenberg, MD, PhD, director of the Cincinnati Center for Eosinophilic Disorders and the Division of Allergy and Immunology. Rothenberg, and colleagues in the Divisions of Gastroenterology, Hepatology and Nutrition; Human Genetics; and the Center for the Genetics Autoimmune Etiology, probed millions of genetic variants in nearly 1,000 people with EoE and 9,000 people without EoE. They found several genetic linkages, with the strongest associations being at the CAPN14 and TSLP loci.

EoE is triggered by allergic sensitivity to certain foods and an accumulation of eosinophils, specialized immune cells, in the esophagus. Rothenberg and his team found that CAPN14, which encodes the enzyme calpain 14 in the esophagus, is dramatically upregulated when epithelial cells in the esophagus are exposed to IL-13, a known molecular activator of EoE. The CAPN14 gene is part of the esophageal disease process of EoE.

CAPN14’s upregulation, Rothenberg’s team noted, occurs in an epigenetic “hot spot” that encodes for an EoE-associated genetic variant that regulates the binding of transcription factors to the upstream region of the CAPN14 gene.

This new finding “is a breakthrough for this condition and gives us a new way to develop therapeutic strategies by modifying the expression of calpain 14 and its activity,” Rothenberg says. “Our results are immediately applicable to EoE and have broader implications for understanding eosinophilic disorders, as well as allergies, in general.”