Crohn’s disease: Discovery of two subtypes could lead to better treatments

Crohn’s disease is notoriously difficult to treat due to the course and severity of the disease varying from one case to another. Research by University of North Carolina School of Medicine has discovered two subtypes of the disease – with different gene expressions and clinical features – which may reveal why such variations in disease progression surface between patients.

The discovery of two classes of Crohn’s has implications for scientists to deliver more targeted treatments.

Crohn’s disease – a long-term condition that causes inflammation to the lining of the digestive system – affects almost 1 million people in the United States. While there is no cure for Crohn’s, treatment with anti-inflammatory drugs and immune system suppressors can help improve symptoms.

Around 70 percent of people with Crohn’s will eventually require surgery to remove damaged portions of the digestive tract and reconnect to healthy sections, and as many as 39 percent will require repeated surgery. Surgery may also close fistulas and drain abscesses.

The study findings – published in the journal Gut – build upon existing knowledge of the biology of Crohn’s disease, and they could potentially lead to more effective strategies and personalized treatments to target the debilitating gastrointestinal condition.

“The one-treatment-fits-all approach doesn’t seem to be working for Crohn’s patients,” says co-senior study author Dr. Shehzad Z. Sheikh, Ph.D., assistant professor in University of North Carolina’s (UNC) departments of medicine and genetics.

“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,” he adds.

Genes that varied between subtypes distinguish colon from ileum

With co-senior author Terry Furey, Ph.D., associate professor in UNC’s departments of genetics and biology, Sheikh and team analyzed colon tissue samples that looked healthy and non-inflamed in 21 Crohn’s patients who had undergone surgery. They then mapped levels of gene expression patterns amongst the samples, finding that there were two distinct groups.

“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 – the healthy tissue from Crohn’s patients and the inflamed samples from Crohn’s patients,” says Furey.

Co-first author Jeremy Simon, Ph.D., a research assistant professor in UNC’s department of genetics, notes that how the two disease subtypes differed was surprising.

Despite the samples being colon biopsies, Simon says, many of the genes that were varied between the two Crohn’s subtypes were markers that distinguish the colon from the ileum – the portion of the small intestine that empties into the colon and is usually the first area to be affected by Crohn’s disease.

The pattern of gene expression in one of the disease subtypes resembled healthy colon tissue. However, the gene expression in the second subtype resembled patterns seen in the ileum.

In addition to analyzing gene expression in the sampled tissue, Sheikh and colleagues observed indicators of the epigenetic state of the DNA tissue that can permit or repress nearby gene activity. The team saw a distinction between the two Crohn’s subtypes in the results that suggest the differences in gene expression emerge from variations in the core programming of the affected cells.

Crohn’s subtypes linked to two different clinical illness patterns

The researchers ensured that the fact that the samples were from adults who had undergone surgery did not skew the results, due to treatment and disease histories, by comparing their data to another dataset.

The team examined data from 201 children who had recently been diagnosed with Crohn’s and had not yet been treated. While the tissue samples in the data were from the ileum, the same colon-like and ileum-like disease classes were observed.

“This suggests that these molecular programs or baseline genomic signatures of Crohn’s subtypes exist independently of patients’ ages or treatment histories,” says Sheikh. He also points out that the two signatures are linked to different patterns of clinical illness.

For example, patients with the colon-like subtype were more likely to be characterized by gut inflammation found during colonoscopy, rectal disease, and colon inflammation severe enough to require colon removal.

In future work, Sheikh, Furey, and collaborators aim to develop a diagnostic test for use on tissue or blood samples taken from routine colonoscopies. By identifying which Crohn’s subtype a patient has, healthcare providers can determine the best therapy for treatment.

Scientists find new genetic locations for type 2 diabetes

Scientists from University College London and Imperial College London in the United Kingdom have identified new genetic locations that might make some people more prone to developing type 2 diabetes.

Scientists identify 111 new genetic locations that indicate susceptibility to type 2 diabetes.

Type 2 diabetes affects hundreds of millions of people worldwide, and the numbers have skyrocketed in recent years. According to the World Health Organization (WHO), the number of people with diabetes has almost quadrupledin the past few decades, from 108 million in 1980 to 422 million in 2014.

In the United States, 29 million people currently have diabetes, and 86 million are thought to have prediabetes.

Until now, researchers were aware of 76 chromosomal locations, or “loci,” that underlie this metabolic disease. However, new research analyzed the human genome further and found an additional 111.

The new study – published in the American Journal of Human Genetics – was co-led by Dr. Nikolas Maniatis of University College London’s (UCL) Genetics, Evolution, and Environment department, together with Dr. Toby Andrew of Imperial College London’s Department of Genomics of Common Disease.

Identifying the type 2 diabetes genetic loci

Using a UCL-developed method of genetic mapping, Maniatis and team examined large samples of European and African American people, summarizing 5,800 cases of type 2 diabetes and almost 9,700 healthy controls.

They found that the new loci – together with the ones previously identified – control the expression of more than 266 genes surrounding the genetic location of the disease.

Most of the newly discovered loci were found outside of the coding regions of these genes, but within so-called hotspots that change the expression of these genes in body fat.

Of the newly identified 111 loci, 93 (or 84 percent) were found in both European and African American population samples.

After identifying genetic loci, the next step was to use deep sequence analysis to try to determine the genetic mutations responsible for the disease.

Gene mapping finds areas associated with diabetes-causing genetic loci

Maniatis and colleagues used deep sequencing to further examine three of the cross-population loci with the aim of identifying the genetic mutations. They then investigated a different sample of 94 Europeans with type 2 diabetes, as well as 94 healthy controls.

The researches found that the three loci coincided with chromosomal regions that regulate gene expression, contain epigenetic markers, and present genetic mutations that have been suggested to cause type 2 diabetes.

Dr. Winston Lau, of UCL’s Genetics, Evolution, and Environment department, explains the significance of these findings:

“Our results mean that we can now target the remaining loci on the genetic maps with deep sequencing to try and find the causal mutations within them. We are also very excited that most of the identified disease loci appear to confer risk of disease in diverse populations such as African Americans, implying our findings are likely to be universally applicable and not just confined to Europeans.”

Dr. Maniatis also highlights the contribution their study brings to the research community:

“No disease with a genetic predisposition has been more intensely investigated than type 2 diabetes. We have proven the benefits of gene mapping to identify hundreds of locations where causal mutations might be across many populations, including African Americans. This provides a larger number of characterized loci for scientists to study and will allow us to build a more detailed picture of the genetic architecture of type 2 diabetes,” says the lead author.

Dr. Andrew also adds, “Before we can conduct the functional studies required in order to better understand the molecular basis of this disease, we first need to identify as many plausible candidate loci as possible. Genetic maps are key to this task, by integrating the cross-platform genomic data in a biologically meaningful way.”