Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic relapsing inflammatory disorder with rising global prevalence. Anti-TNF therapy is widely used as a first-line biologic treatment, yet a substantial proportion of patients fail to achieve early clinical remission. Predictive biomarkers for treatment response are therefore of considerable clinical interest, but robust genetic markers have remained largely undefined.
To investigate genetic determinants of anti-TNF response, we analyzed nine discovery cohorts from Denmark, Austria, and Germany including IBD patients treated with anti-TNF as their first biologic therapy. Two independent cohorts from Germany and the United States were used for replication. For each IBD subtype, we performed genome-wide single-variant association analyses, followed by fine-mapping and colocalization, and complemented these analyses with gene-based association testing. We additionally applied cross-phenotype meta-analysis to explore shared genetic signals across CD and UC. To place loci emerging from the genetic analyses into a disease-relevant biological context, we integrated publicly available single-cell RNA-seq data from the scIBD database and assessed expression patterns across healthy and inflamed intestinal tissue states.
This study establishes an analytical framework for the discovery and biological contextualization of genetic factors associated with anti-TNF treatment response in IBD.

Co-authors: Johan Burisch, Vibeke Andersen, Walter Reinisch, David Ellinghaus