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OP004 Gene expression profiling indicates similar molecular pathways are active in adult and paediatric Crohns disease

A. Stojmirovic*, R. Dobrin, R. Strauss, D. Chan, K. Li, J. Friedman

Janssen R & D, LLC, Spring House, Pennsylvania, United States

Background

The development of new medical therapies for paediatric CD typically requires extrapolation of efficacy from adults and is contingent on similar pathogenesis in both groups. Children with CD at presentation have more disease that is more extensive, but genome-wide association studies have not identified pathways that distinguish these 2 populations. At the level of mRNA expression, little is known regarding adult vs paediatric CD.

Methods

Three RNA–expression datasets were analysed:

1) CERTIFI: 239 ileal and colonic biopsies obtained from a phase 2b study of ustekinumab use in adults with CD; also includes 28 biopsies from normal healthy subjects.

2) GSE10616: 40 colonic biopsies from subjects with paediatric-onset CD and in healthy controls.

3) GSE57945: 319 ileal biopsies from treatment-naïve paediatric CD patients and non-inflammatory bowel disease (IBD) controls.

Expression profiles of diseased biopsies were compared with controls. Comparisons were made using a moderated t-test, and multiple testing adjustment of p-values was obtained by conversion to false discovery rate (FDR). Differential expression profiles were globally compared using the cosine similarity of the vectors of their log-fold-change (logFC) values. The Reactome and WikiPathways databases were queried for enrichment in differentially expressed genes using the SaddleSum tool with logFC values as gene weights and E-value < 0.01 as a cut-off.

Results

Differentially expressed genes and their associated pathways clustered according to anatomical location (ileum or colon), with adult and paediatric types clustering together. A universal inflammation motif was evident, comprising chemokines and cytokines and their receptors, extracellular matrix, GPCR signalling, and type-II interferon signalling. In ileal CD, the effect sizes observed in the inflammation signatures in the paediatric population were stronger than in adults, although the direction of affected genes was strongly consistent in both cases. This was also reflected in pathway analysis of down-regulated genes, where pathways enriched in the paediatric signatures overlapped extensively with those observed in adult ileal CD. Strong similarity was also observed between colonic CD differential expression profiles based on log-fold changes in adults and children, but the paediatric CD colon signature contained very few significantly differentially expressed genes, making additional inference difficult.

Conclusion

The gene signatures for both children and adults are strongly similar. These findings suggest a common molecular profile and disease process in both populations and lend support to the extrapolation of efficacy from adults to children in the development of new medical therapies for CD.