Study finds that Crohn’s disease appears to have two distinct genetic subtypes
Crohn’s disease, a common inflammatory disorder of the intestinal tract, is known to have life threatening consequences, interfering with individuals’ quality of life and is extremely difficult to treat with positive outcomes. This is because the severity varies a lot from one person to another.
UNC School of Medicine scientists have now made a discovery that may be able to explain why Crohn’s is so variable. Why? It appears that the disease has at least two distinct subtypes. Each of them has its own pattern of gene expression as well as the mix of clinical features.
This discovery was published in the journal called ‘Gut’. With this new information its possible to have far more effective strategies for treating Crohn’s Disease.
You see, although people with the disease are usually treated with powerful immune-suppressing drugs, about 70% eventually resort to surgery to remove parts of the intestinal tract that may have developed blockages or some other problems that are caused by the rampant inflammation. Unfortunately, even after surgery, the disease often recurs and so surgery is not curative.
Shehzad Z. Sheikh, MD, PhD, is assistant professor in UNC’s departments of medicine and genetics and co-senior author of the study. He says, “The one-treatment-fits-all approach doesn’t seem to be working for Crohn’s patients. 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.”
Dr Sheikh has teamed up with Terry Furey, PhD, associate professor in UNC’s departments of genetics and biology and study co-senior author, to map the levels of gene expression in non-inflamed, healthy-looking colon tissue samples taken from 21 Crohn’s patients. When they began looking at the gene expression patterns in these patients, two clear groupings dominated.
Fury says, “Although we saw a difference between the Crohn’s samples and samples from people without Crohn’s, we saw an even greater difference at the molecular level between these two subsets of the Crohn’s samples.”
They were surprised by how the two disease subtypes differed.
Jeremy Simon, PhD, a research assistant professor in UNC’s department of genetics and co-first author of the study with former graduate student Matthew Weiser, PhD. says, “It was surprising. 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 team described how in one disease subtype, the pattern of gene expression mostly resembled that of normal colon tissue where as in the other, the gene expression shifted towards the pattern normally seen in the ileum. The ileum is that part of the small intestine that empties into the colon via the cecum, and is often the first area that is affected in Crohn’s Disease.
Not only did the team look at specific gene expression products in the sampled tissue, but also looked at indicators of the “epigenetic” state of the tissue DNA. This is the pattern of molecular switches on chromosomes that effectively permit or repress nearby gene activity.
Again there was a distinction between the two Crohn’s Disease subtypes which implies that their differences in gene expression stemmed from differences in the basic programming of the affected cells.
The colon samples were taken from adults with Crohn’s who had all undergone surgery. This left the possibility that both their treatment and their disease histories may have played a role in the gene expression patterns they saw.
So the team subsequently looked at a recently published gene expression dataset from 201 children who were newly diagnosed with Crohn’s Disease and had never been treated. Although the tissue samples this time were from the ileum, the researchers again saw the same two colon-like and ileum-like disease classes.
Dr Sheikh says that this suggests that these molecular programs or baseline genomic signatures of Crohn’s subtypes exist independently of patients’ ages or treatment histories.
What was very significant is that these two so called ‘signatures’ were linked to different patterns of clinical illness.
The “colon-like” cases were more likely to have gut inflammation visible during colonoscopy, rectal disease that is very difficult to manage from a clinical standpoint and severe enough colon inflammation to require surgical removal of the colon.
Dr Sheikh, Furey, and their colleagues are aspiring to translate these results into a diagnostic test on tissue samples that they will get from routine colonoscopies, or maybe even on blood samples. These types of tests could help doctors to classify their patients suffering with Crohn’s Disease and so be able to select the best therapies.
They have received funding from the National Institutes of Health (NIH). Their plan for their initial follow-up is to conduct a broadened study to be able to confirm their findings in a much larger set of patient samples.
They also have plans to do a long-term study, in which they will test patients for their Crohn’s subtype when they are first diagnosed with Crohns and then follow them for many years to see whether the assigned subtype predicts their disease course.
“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. The idea is to find the best therapeutic course for each patient as quickly and efficiently as possible,” concludes Dr Sheikh.
Published on October 14, 2016 at 11:49 AM