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Crohn's disease may have two distinct genetic subtypes

Source/Disclosures Source: Weiser M, et al. Gut. 2016;doi:10.1136/gutjnl-2016-312518. ADD TOPIC TO EMAIL ALERTS Receive an email when new articles are posted on . Please provide your email address to receive an email when new articles are posted on Subscribe ADDED TO EMAIL ALERTS You've successfully added to your alerts. You will receive an email when new content is published.



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Crohn’s disease may have at least two distinct genetic subtypes that are associated with their own specific clinical features, according to researchers from the University of North Carolina School of Medicine.

These findings, published online today in Gut, could provide a molecular explanation for the heterogeneity of disease course and severity observed in Crohn’s disease, and potentially guide more customized treatment options.

Shehzad Z. Sheikh



“The one-treatment-fits-all approach doesn’t seem to be working for Crohn’s patients,” Shehzad Z. Sheikh, MD, PhD, assistant professor in UNC’s departments of medicine and genetics, said in a press release. “It’s plausible that this is because only a subset of patients has the type of disease that responds to standard therapy, whereas, for the rest of the patients, we’re really not hitting the right targets.”

Sheikh and colleagues collected non-inflamed, healthy looking colonic mucosa samples from 21 Crohn’s patients and 11 controls without IBD. Then they analyzed gene expression using RNA sequencing, and gene regulation based on chromatin accessibility using formaldehyde-assisted isolation of regulatory elements.

The gene expression analysis showed a “striking clustering pattern,” revealing two distinct groups of Crohn’s patients, and the differential expression of the genes involved was unexpected, according to the release. Crohn’s disease samples that resembled those of the non-IBD controls showed abundant expression of colon-specific genes, while the other subtype showed ileum-specific gene expression patterns.

“It was surprising,” Jeremy Simon, PhD, a research assistant professor in UNC’s department of genetics, said in the press release. “Many of the genes that were different between the two Crohn’s subtypes are markers that distinguish the colon from the ileum, despite these being colon biopsies.”

The genetic regulation analysis also showed distinction between the two subtypes, suggesting that regulatory activity contributes to the differential colon-like and ileum-like gene expression.

As the gene expression profiles of adult Crohn’s patients may vary based on their treatment history, the researchers sought to confirm their findings by examining previously published gene expression data from ileal biopsy samples collected from 201 treatment-naive pediatric Crohn’s patients and 40 non-IBD controls. While not as distinct as with the adult samples, the researchers observed the same two colon-like and ileum-like subtypes.

“This suggests that these molecular programs or baseline genomic signatures of Crohn’s subtypes exist independently of patients’ ages or treatment histories,” Sheikh said in the press release.

Further analyses showed key expression differences in in cellular metabolism and immune pathways.

In addition, retrospective analysis of the pediatric samples showed the subclasses were associated with distinct clinical characteristics and outcomes. Patients in the colon-like subgroup were more likely to have both colon and ileum involvement, deep ulcers, macroscopic inflammation, greater rectal disease involvement and eventual need for colectomy. Patients in the ileum-like subgroup were more likely to show no inflammation, have colon-only involvement, have ileal disease and need for postoperative treatment with biologics.

The researchers plan to develop a diagnostic test based on these results to better classify Crohn’s disease patients and optimize therapies.

“We hope one day to be able to test Crohn’s patients for the subtype of the disease they have, and thus determine which treatment should work best,” Sheikh said in the press release. “The idea is to find the best therapeutic course for each patient as quickly and efficiently as possible.” – by Adam Leitenberger

Disclosures: The researchers report no relevant financial disclosures.