Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication of the 5q22 locus (meta-analysis p = 1.9×10−16), we identified association at 2p23 (encoding CAPN14, p = 2.5×10−10). CAPN14 was specifically expressed in the esophagus, dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13, and located in an epigenetic hotspot modified by IL-13. There was enriched esophageal expression for the genes neighboring the top 208 EoE sequence variants. Multiple allergic sensitization loci were associated with EoE susceptibility (4.8×10−2 < p < 5.1×10−11). We propose a model that elucidates the tissue specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14.

Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity

“…Accordingly, SYNPO expression is highly correlated with a subset of esophageal-enriched genes involved in epithelial differentiation. Notably, the majority of these genes are downregulated in EoE, except CAPN14, which is considered to be a genetic driver of the disease and is linked to epithelial differentiation (14,53,54). These data further support that SYNPO dysregulation is a part of a broader alteration in esophageal epithelial differentiation program in response to IL-13.…”

“…Most findings that underscore the critical role of IBF in pathogenesis of EoE have focused on structural epithelial proteins, such as DSG1, or proteases, such as CAPN14 (11,14,53). Our findings -that actin-associated proteins are significantly upregulated in EoE, correlate with EoE severity, and alter esophageal epithelial integrity in cultured cells -signify the potential involvement of SYNPO and other actin-binding proteins in the pathogenesis of EoE.…”

“…Structural and transcriptional changes observed in the inflamed epithelium in biopsies from patients with EoE can be recapitulated in vitro by treating esophageal epithelial cells with IL-13 (10)(11)(12)(13). IL-13 is thought to mediate these responses through epigenetic changes, including elevated levels of histone acetylation and decreased DNA methylation in the promoters of critical mediators, such as eotaxin 3 (also known as CCL26), CAPN14, and NTRK1 (14)(15)(16). Co-occurrence of epigenetic changes with transcriptional response suggests that integrating transcriptional and epigenetic analyses may serve as a useful approach to discover molecules with functional roles in EoE pathogenesis, especially since EoE is influenced by gene-environment interactions (17).…”

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

“…The CCHMC controls were diagnosed with eosinophilic esophagitis, had an age range of 2-52, and had Illumina Omni5 SNP chip data available from dbGAP (project "Better Outcomes for Children: GWAS from Cincinnati Children's Hospital Medical Center (CCHMC) -eMERGE Phase II data"; phs000494.v1.p1) 88 . The Columbia University controls were confirmed as being of European ancestry by questionnaire during recruitment, have been used as controls for studies of age-related macular degeneration (AMD) as described previously 72,89,90 , were of an advanced age (mean age 74.8±7.1 years), did not exhibit any distinguishing signs of macular/retinal disease after clinical examination by trained ophthalmologists, and had no known family history of retinal disease.…”

Eosinophilic esophagitis

“…Eotaxin-3 (CCL26) 25 followed by Thymic stromal lymphoprotein (TSLP) 26,27 located on chromosome 5q22 were the first susceptibility genes associated with EoE. Other genetic loci include two loci which have previously been associated with other atopic and autoimmune diseases (c110rf30 28,29 and STAT6 28,30 ) and two EoE specific loci; ANKRD27 28,31 (regulates trafficking of melanogenic enzymes to epidermal melanocytes) and CAPN14 28,32 which encodes a calcium binding protease (calpain) that is specific to esophagus.…”