Genetics of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with marked mucosal eosinophil accumulation. EoE disease risk is multifactorial and includes environmental and genetic factors. This review will focus on the contribution of genetic variation to EoE risk, as well as the experimental tools and statistical methodology used to identify EoE risk loci. Specific disease-risk loci that are shared between EoE and other allergic diseases (TSLP, LRRC32) or unique to EoE (CAPN14), as well as Mendellian Disorders associated with EoE, will be reviewed in the context of the insight that they provide into the molecular pathoetiology of EoE. We will also discuss the clinical opportunities that genetic analyses provide in the form of decision support tools, molecular diagnostics, and novel therapeutic approaches.

Figure 1

Concordance of disease in siblings supports role of genetic and environmental etiologic factors for EoE risk. DZ, dizygotic; EoE, eosinophilic esophagitis; G × E, gene-by-environment; MZ, monozygotic. (From ref. .)

Figure 2

Results of a genome-wide association study of EoE. Data from 736 subjects with EoE and 9,246 controls over 1,468,075 common genetic variants are graphed in a Manhattan plot. The −log₁₀ P-value of each probability is shown as a function of genomic position on the autosomes. Genome-wide significance (red dashed line; P = 5 × 10⁻⁸) and suggestive significance (solid blue line; P = 1 × 10⁻⁷) are indicated. CAPN14, Calpain-14; HSF2BP, Heat Shock Transcription Factor 2 Binding Protein; LRRC32, Leucine Rich Repeat Containing 32; MIR4675, microRNA 4675; TSLP, Thymic stromal lymphopoietin; XKR6, XK Related 6. (From ref. .)

Figure 3

Eosinophilic esophagitis (EoE)-risk loci contain genes with known roles in the pathoetiology of EoE. Esophageal epithelial cells secrete thymic stromal lymphopoietin (TSLP, encoded by EoE-risk locus 5q22) and interleukin-33 (IL-33) in response to stimuli from various environmental factors. These cytokines act on T-helper cells, leading to their secretion of allergic cytokines including IL-13, IL-4, and IL-5. IL-5 signals primarily through signal transducer and activator of transcription 5 (STAT5) in eosinophils to promote tissue recruitment and survival. IL-13 signals primarily through signal transducer and activator of transcription 6 (STAT6, encoded by EoE-risk locus 12q13) and promotes the transcription of calpain-14 (CAPN14, encoded by EoE-risk locus 2p23) and C-C Motif Chemokine Ligand 26 (CCL26, also known as eotaxin-3). STAT6-dependent IL-13 signaling also leads to decreased expression of the tight junction protein desmoglein 1 (DSG1). Altogether, these signaling pathways lead to eosinophil recruitment and survival, a disrupted esophageal epithelial barrier, and a disorganized esophageal epithelium.