TGFβ1 Promoter SNP C-509T Increases TGFb1 Expression and Alters Cellular Function in Eosinophilic Esophagitis
Sunday, March 4, 2018
South Hall A2 (Convention Center)
Loan D. Duong, BS, Renee Rawson, BS, Braxton Bell, Seema Sharma Aceves, MD PhD FAAAAI
RATIONALE: Eosinophilic Esophagitis (EoE) is a chronic allergic disease characterized by esophageal inflammation and fibrosis. The functional TGFβ1 promoter SNP C-509T associates with asthma and renal fibrosis. Our data shows that TGFβ1 genotype TT associates with more severe histologic disease in the pediatric EoE esophagus. However, the mechanism by which TT genotype may promote more severe EoE phenotype is unclear.
METHODS: Primary fibroblasts were isolated from patient biopsies of CC (n=4) and TT genotypes (n=3) with active disease. Baseline and TGFβ1 induced gene expression from CC versus TT fibroblasts was analyzed using qPCR. Primary esophageal epithelial cells from human donors were used in organoids and barrier function studies. Paraffin embedded esophageal biopsies were stained for E-Cadherin and claudin-1 proteins by genotype.
RESULTS: Fibroblasts from TT genotype patients had significantly higher baseline TGFβ1 (p = 0.008) and collagen (p=0.018) mRNA expression compared to CC genotype patients. In contrast, collagen (p=0.016) and periostin (p=0.002) were more highly induced by TGFβ1 treatment in CC genotype fibroblasts. Consistent with a more severe histologic phenotype, esophageal biopsies from TT genotype patients demonstrated significantly less membrane bound E-cadherin (p= 0.002) and claudin-1 (p = 0.001) than CC genotype patients. Stratified primary epithelial cells treated with TGFβ1 demonstrated both decreased E-cadherin localization and reduced epithelial barrier resistance.
CONCLUSIONS: Patients with TT genotype at TGFβ1 SNP C-509T may have more severe EoE due to increased TGFβ1 expression leading to decreased epithelial barrier function and altered fibroblast function.