Supplementary Figure 8: Proposed model of increased EoE risk at the CAPN14 locus.
CAPN14 is expressed specifically in the esophagus (Fig. 2a). Allergic inflammatory mediators including IL-13 and IL-4 induce CAPN14 expression and activity (Figs. 2h and 3a and refs. 36, 37), and regulation of increased expression is mediated in part through the acetylation of histones (Fig. 2i). The abundance of IL-13 and IL-4 in the esophagus of patients with EoE5–8results in increased CAPN14 expression (Fig. 2b–d) and activity (Fig. 3b), and the calpain activity of CAPN14 potentially attenuates further inflammation by digesting endogenous proteins. The genetic variants associated with EoE risk at the CAPN14 locus lead to decreased CAPN14 expression (Fig. 2e) feasibly through the binding of a protein (Fig. 2j), a transcription factor that potentially acts as a transcriptional repressor. Together, our data are consistent with a model (a) in which CAPN14 is induced along with other anti-inflammatory agents such as microRNAs, cell surface receptors and T regulatory cells. (b) When exposed to IL-13 and IL-4, chromosomes in epithelial cells with the CAPN14 EoE risk allele are unable to induce CAPN14 expression to the extent of chromosomes with the non-risk allele. We propose a model in which the allelic change in CAPN14 expression dysregulates a critical negative feedback loop in the esophagus resulting in increased risk of pathology and EoE.
