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Background:Genome-wide association studies have linked single nucleotide polymorphisms (SNPs) to risk of inflammatory bowel disease (IBD). Yet, the majority of IBD-associated risk SNPs tag non-coding regions of the genome, with more than 1000 genes encoded within the risk loci. In addition to ongoing fine mapping of risk loci and exome sequencing studies, the study of gene expression and characterization of expression quantitative trait loci (eQTL) help to refine candidate genes in risk loci. Because the genetic effects are likely to be disease context-specific, we examined gene expression in biopsies and resected tissue from uninflamed and inflamed terminal ileum (TI) and colon from genotyped patients with Crohn’s disease (CD) and ulcerative colitis (UC). Methods:We designed a custom probe set on the NanoString digital gene expression platform capturing 678 genes encoded within IBD-associated risk loci and profiled 1100 tissue samples (including 178 paired uninflamed and inflamed samples) from 593 patients and healthy controls. Patients were genotyped on the Illumina ImmunoChip array, and we performed focused analysis of IBD-associated risk loci. We developed and applied an analytical framework including principal components analysis, differential expression, machine learning algorithms, and eQTL analysis to characterize inflammation signatures for CD and UC (specific or common to CD and UC), gene-gene interactions, and significant SNP-gene associations. Results:Differential expression of a subset of our genes readily discriminated TI and colon tissues, with FAM55A, a gene encoded in a UC-specific risk loci, most highly differentially expressed (180–190 fold relative expression in the colon compared to TI). Genes with the lowest variance in expression across healthy controls were the same genes with the greatest variance in patients, suggesting that mechanisms exist to tightly regulate the expression of these genes in homeostasis and increased variance of expression in disease states may reflect a loss of such regulatory mechanisms. Unique and shared inflammatory signatures between CD and UC were identified, including genes that exhibit a continuous gradient of increasing expression from healthy controls to uninflamed and inflamed IBD tissues (e.g., SLC11A1, CCL11, CDH3). Examining patterns of gene co-expression, we found a network of 41 genes, enriched for B cell signaling, with conserved co-expression across TI and colon, CD and UC, and inflammation subtypes, highlighting possible novel interactions between a subset of risk genes, including SP140 and PTPRC. In addition to cis- and trans-eQTLs specific to CD and UC, paired uninflamed and inflamed tissues from the same patient allowed characterization of fold-change eQTLs, demonstrating how IBD-associated risk SNPs may contribute to risk of disease through the modulation of a gene expression change under inflammatory conditions. Conclusions:This study demonstrated colon/TI-, CD/UC-, and inflammation-specific expression of IBD-associated risk genes, and, for a subset of genes, genotype-specific patterns of expression. These data prioritize candidate genes for functional characterization in 60% of IBD-associated risk loci. This analytical framework has relevance for the study of genetic variation associated with other complex, polygenic autoimmune and inflammatory diseases, underscoring the value of study in disease-relevant tissues and in the context of active disease.

inflammatory bowel diseases

O-002 Genes in IBD-Associated Risk Loci Demonstrate Genotype-, Tissue-, and Inflammation-Specific Patterns of Expression in Terminal Ileum and Colon Mucosal Tissue