TGFβ1 Single Nucleotide Polymorphism C-509T Alters Mucosal Cell Function in Pediatric Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) associates with elevated numbers of esophageal TGFβ1 expressing cells. We utilized esophageal biopsies and fibroblasts from TT genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP-2 (p<.05) gene expression and distinct contractile properties compared with CC genotype (n=6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p<.05). Esophageal biopsies from TT genotype subjects had significantly less epithelial membrane bound E-cadherin (p<.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p<.001) and E-cadherin localization (p<.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients.