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Molecular classification of Crohn’s disease reveals two clinically relevant subtypes

ABSTRACT: Objective: The clinical presentation and course of Crohn’s disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes. Design: We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult CD and control patients. To support the generality of our findings, we analyzed previously published expression data from a large cohort of treatment-naïve pediatric CD and control ileum. Results: We found that adult CD patients clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Further, gene expression from the ilea of the treatment-naïve pediatric CD patient cohort could be similarly subdivided into colon- and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behavior, including rectal and perianal disease and need for colectomy. Conclusion: Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85499 | GEO | 2016/12/11

SECONDARY ACCESSION(S): PRJNA338668

REPOSITORIES: GEO

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Project description:The course of Crohn's disease (CD) is heterogeneous, confounding effective personalized therapy. A previous analysis of differences in gene expression between patients with versus without CD groups revealed 2 subsets of patients with CD -- a group characterized by genes more highly expressed in the colon (colon-like CD) and a group with increased expression of ileum marker genes (ileum-like CD). We compared differences in microRNAs between these groups. We performed genome-wide microRNA profile analyses of colon tissues from 18 adults with CD and 12 adults without CD (controls). We performed principal component analyses to associate levels of microRNAs with CD subtypes. Colonic epithelial cells and lamina propria immune cells were isolated from intestinal tissues and levels of microRNA 31 (miR-31) were measured by real-time quantitative PCR. We validated the differential expression of miR-31 between the subtypes by measuring miR-31 levels in an independent cohort of 32 adult patients with CD and 23 controls. We generated epithelial colonoid cultures from controls and patients with CD, and measured levels of miR-31 in crypts. We performed genome-wide microRNA profile analyses of formalin-fixed paraffin-embedded colon and ileum biopsies from 76 treatment-naive pediatric patients with CD and 51 controls (234 samples) and collected data on disease features and outcomes. In comparing miRNA expression profiles between 9 patients with colon-like CD and 9 patients with ileum-like CD, we identified 19 miRNAs with significant differences in levels. We observed a 13.5-fold difference in level of miR-31-5p between tissues from patients with colon-like vs. ileum-like CD (Padj = 1.43 x 10-18). Principal component analysis found miR-31 to be the top contributor to the variance observed. Levels of miR-31 were increased 60-fold in tissues from patients with ileum-like CD compared with controls (Padj = 2.59 × 10-51). We validated the differential expression of miR-31 between the subtypes in the independent set of tissues. Colonoids derived from patients with CD had significantly higher levels of miR-31 than colonoids derived from control tissues (day 2 P=.041 and day 6 P=.0095). Levels of miR-31 were significantly increased in colon tissues from pediatric patients with CD compared with controls (~7.8-fold, P=4.64 ×10-7) and in ileum tissues from patients with CD patients vs. controls (~1.5-fold, P=9.97 × 10-7). A high level of miR-31 in index biopsies from pediatric patients with only inflammation and no other complications at time of diagnosis associated with development of fibrostenotic ileal CD. We identified differences in miR-31 levels in colon tissues from adult and pediatric patients with CD compared with controls, and in patients with ileum-like CD compared with colon-like CD. Further studies are needed to determine the mechanisms by which miR-31 might contribute to pathogenesis of this subtype of CD, or affect response to therapy.

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Molecular classification of Crohn’s disease reveals two clinically relevant subtypes

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