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PTH-099 Distinctive Gene Expression Profiles in the Whole Blood of Patients with Moderate to Severe Ulcerative Colitis and Crohn’S Disease
  1. S Telesco1,
  2. K Li1,
  3. C Marano1,
  4. C Gasink1,
  5. K Ma1,
  6. R Strauss1,
  7. C Brodmerkel1
  1. 1Janssen R&D, LLC, Spring House, United States

Abstract

Introduction The aim of this study was to define whole blood (WB) gene expression profiles in moderate to severe ulcerative colitis (UC) and Crohn’s disease (CD) patients, and to elucidate modulated genes and pathways that are shared by and also unique to each disease. Gene expression profiling of UC and CD WB has not been compared in a study of this size, and the subset of non-overlapping genes identified could potentially lead to a means to discriminate between these two forms of IBD. A molecular diagnostic assay based on gene expression from readily accessible tissue (WB) would have great utility in differentiating between UC and CD, a common diagnostic dilemma.

Methods WB samples were collected from a subset of patients in one of two clinical trials: PURSUIT-SC, a study to evaluate safety and efficacy of induction therapy with SC golimumab in patients with moderate to severe UC, and CERTIFI, a study to evaluate safety and efficacy of ustekinumab therapy in patients with moderate to severe CD. In both studies, samples (n = 69 UC, 204 CD) were collected at baseline for mRNA expression profiling using Affymetrix HG-U133+ PM arrays. Samples from healthy volunteers were obtained independently of the trials. Changes in gene expression of > 1.5-fold and false detection rate (FDR) p-value < 0.05 were considered significant.

Results There was overlap in the significant changes in gene expression observed in the WB of UC and CD patients compared to normal controls. Of the 1229 differentially expressed transcripts in UC, 63% (45% relative to CD) overlapped with those in CD WB. Over-expressed genes in UC and CD included CD177, IL1R1, IL17RA, MMPs, and other genes involved in systemic inflammation, cellular cytotoxicity, and lymphocyte migration. However, significant proportions of genes (37% of UC gene changes, or 55% of CD) were uniquely expressed in either disease. Genes expressed specifically in UC included regulators of cell death and survival, eg BCL2A1, and several integrin isoforms. Differentially expressed genes specific to CD included IL23A, genes involved in ubiquitination and autophagy, eg ATG9B, and several chemokines. Pathways unique to CD involved B-cell receptor signalling and protein degradation, while oncogenic mechanisms were more predominant in pathways uniquely upregulated in UC.

Conclusion Despite sharing many of the same upregulated transcripts, WB of CD and UC patients also demonstrated significant proportions of differentially expressed genes. Transcriptional profiles in circulating immune cells found in WB may serve as a surrogate for relaying the state of less-accessible luminal tissues in UC and CD patients, and have the potential to aid in differential diagnosis of these diseases.

Disclosure of Interest S. Telesco Employee of: Janssen R&D, LLC, K. Li Employee of: Janssen R&D, LLC, C. Marano Employee of: Janssen R&D, LLC, C. Gasink Employee of: Janssen R&D, LLC, K. Ma Employee of: Janssen R&D, LLC, R. Strauss Employee of: Janssen R&D, LLC, C. Brodmerkel Employee of: Janssen R&D, LLC

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