IBD risk locus rs1077773 enhances aryl hydrocarbon receptor activity and modulates immune cell function in vitro

作者：Ashley C. King, Kristen M. Seiler, Kerry Swanson, Matthew A. Ciorba, David M. Alvarado · 发表于：Inflammation Research · 年份：2026 · DOI：10.1007/s00011-026-02236-3 · 被引用次数：1 · 研究领域：Medicine

Introduction The inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) are disorders that cause chronic inflammation of the gastrointestinal tract. Both genetic and environmental factors contribute to the pathogenesis of IBD. There are currently >200 known genetic susceptibility loci for the development of IBD. The physiological impact of the majority of these loci remain a gap in our knowledge. One such locus is the single nucleotide polymorphism rs1077773, located ~56 kbp downstream from the aryl hydrocarbon receptor (AHR) gene. AHR is a ligand-activated transcription factor that is crucial to maintaining intestinal homeostasis. We hypothesized that rs1077773 enhances AHR activity to regulate mucosal immune response and maintain intestinal homeostasis. Methods All study procedures and reagents were approved by the Washington University Institutional Review Board (#202011003). Patient biopsies were collected at Barnes Jewish Hospital and genotyped using the IBD Genetics Consortium custom GSA SNP chip (Broad Institute) followed by imputation using TopMed Imputation Server at University of Michigan. Patient derived organoids (PDOs; N=3 G/G, N=4 G/A, N=5 A/A) were derived and maintained in 3D culture and supplemented with 50% L-WRN conditioned medium with passage every 3–4 days as previously described. PDOs were treated with AHR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) or vehicle for 48 h. Expression of AHR and its transcriptional targets Cytoc...