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Background Disease location is a prominent axis of heterogeneity in Inflammatory Bowel Disease (IBD) with many implications. Using genome-wide profiling of the transcriptome of monocytes and CD4+ T cells isolated and purified from whole blood, we aimed to identify molecular signatures and mechanisms associated with different locations among IBD patients. Methods Blood was collected from 125 IBD patients (87 CD, 38 UC) with endoscopy-proven active disease (presence of ulcerations). Cell separation and fluorescence activated cell sorting were performed to separate the monocyte and CD4+ T cell fractions, from which RNA was subsequently isolated and sequenced (Illumina HiSeq 4000NGS). We used different supervised and unsupervised approaches (differential expression, pathway based data integration, latent factor based models, regularized generalized canonical correlation analysis and co-expression networks) to interpret the differences in the gene expression datasets of monocytes and CD4+ T cells from patients with different disease locations (Montreal classification). Functional enrichment analysis was performed using the ReactomePA package. Regulatory relationships and therapeutic relevance information were retrieved from the ChEA3 and the OpenTargets resources respectively. Comparison with single-cell and bulk-derived gene expression signatures from other auto-immune diseases were performed using the ADEX resource. Results Highly variant disease-location (DL)-associated genes (FDR &amp;lt;= 0.1) in monocytes and CD4+ T cells were identified using latent factor based unsupervised models. These genes were known to be involved in IBD pathogenesis and/or intestinal inflammation. Additional supervised analysis revealed significant differences in CD4+ T cells between ileal CD patients and UC patients. RAF-independent MAPK-activation pathway and FOXO-mediated transcriptional pathway (downregulated in UC patients) were over-represented (FDR &amp;lt;= 0.05) among the features distinguishing ileal CD and UC patients based on signature sets derived from the above-mentioned multiple approaches. Of note was the finding that 12.5% of the DL associated co-expression modules were also annotated as IBD drug targets. Based on gene expression signature from bulk and single-cell sources, the DL associated genes were found to be active in many other auto-immune diseases such as rheumatoid arthritis, systemic sclerosis, Sjögren’s syndrome, type 1 diabetes and Systemic lupus erythematosus, suggesting their role in mediating immune malfunctions. Conclusion We identified signaling pathways and transcription factors which could drive the expression differences observed in the circulating immune cells between ileal CD and UC patients.

DOP08 Transcriptional signatures of blood derived immune cells associated with disease location-based heterogeneity in IBD