Single-nuclei multiome-seq and modeling of intestinal cell types nominates regulatory mechanisms driving IBD genetic risk and anti-TNF nonresponse 2309915

Abstract

Inflammatory Bowel Disease (IBD) is an autoinflammatory condition, with increasing incidence in children. TNF inhibitor (TNFi) therapy is the only FDA-approved biologic in pediatric IBD, yet only a third of patients achieve mucosal healing with TNFi. We recently identified polygenic risk scores for IBD as a top predictor of TNFi response in an ensemble model integrating the PRS with clinical measurements. The majority of IBD risk variants are noncoding. If causal, they likely alter transcription factor (TF) binding and downstream gene expression in particular cell types and contexts. Using single-nuclei multiome sequencing (snRNA-seq and snATAC-seq) of pediatric IBD intestine from TNFi responders and nonresponders, we generated accessible chromatin maps for 27 cell types, resolved by TNFi response status. CD4 T cells and macrophages were top-ranked mediators of IBD genetic risk, especially in the TNFi non-response context (PMID:38405748). We curated ligand-response gene signatures to identify cell-cell signaling responses (1) targeted by IBD genetic risk variants and (2) altered in TNFi nonresponders. In CD4 T cells, we constructed genome-scale gene regulatory networks (GRNs) (PMID:36945549) to predict TF mediators of IBD genetic risk and TNFi response. Genetic risk colocalization identified Th17 cells and inflammatory monocytes/macrophages as key mediators of IBD risk. In Th17 cells, GRN modeling revealed TF activities associated with TNFi nonresponse, including IBD risk enhancer targets (e.g., CREM, GFI1) and TFs downstream of signaling pathways targeted by next-gen IBD therapeutics (e.g., STAT4 downstream of IL23/IL12). While, in macrophage, IBD risk variant targets and TNFi-nonresponse gene signatures were linked to TNF and IL1 signaling. Our integrated modeling nominates cell-type-specific regulatory mechanisms linking IBD genetic risk to TNFi non-response and prioritizes next-gen IBD biologic targets. Cincinnati Children’s Research Foundation by Academic Research Committee (ARC) grant #53671 (ERM, LAD, AGM, LCK, MTW); National Institute of Health (NIH) funding: R01AI153442 (ERM), the CCRF Digestive Health Center grant, P30DK078392 (LAD) Computational and Systems Immunology (COMP)