Morbus Crohn

Although millions of people worldwide suffer from Crohn’s disease, its causes have only been partially elucidated. The study of the genome now offers new starting points. In it, researchers identified ten new Crohn’s disease risk genes that point to previously unknown mechanisms of development. Knowing these processes and the cells involved can help find treatments for previously incurable intestinal disease.

Crohn’s disease is characterized by chronic relapsing inflammation of the gastrointestinal tract. Those affected frequently experience severe diarrhea, abdominal pain, and sometimes vomiting. Medications can relieve symptoms, but there is no cure yet – also because the causes of this intestinal disease have only been partially elucidated. It seems clear that there is a genetic susceptibility and that the intestinal barrier and the mucous membranes of the gastrointestinal tract are pathologically altered in those affected.

Previous genomic association studies (GWAS) have already identified several genomic regions that are altered in Crohn’s patients. However, the functions of these genetic variants are known only in a few cases.

Ten risk genes, six of which are completely new

That’s why Alexis Sazonov of the Wellcome Sanger Institute in England and colleagues now search for risk genes for Crohn’s disease using a slightly different method, known as exome sequencing. Only the protein-coding genes of Crohn’s patients are compared with healthy controls. For the study, the international research team analyzed samples from 30,000 patients from 35 medical centers worldwide and 80,000 controls.

The result: “We have identified genetic variants in ten genes that increase susceptibility to Crohn’s disease,” said co-author Andre Frank of Kiel University. “Changes in six genes were identified in regions that were not previously associated with Crohn’s disease.” The remaining four genes are in areas where GWAS studies have already shown an association with an increased risk of Crohn’s disease.

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Targeting mesenchymal cells

What is interesting, however, is the functions of the newly identified risk genes. Because they provide clues to a previously unknown development mechanism. “Several recently identified genes appear to be related to the role of mesenchymal cells in the physiological homeostasis of the gut,” the scientists explain.

These cells and progenitor cells, which are part of connective tissue in a broader sense, play an important role in the maturation, migration and recruitment of immune cells. On the other hand, the mesenchymal cells of the intestine interact closely with immune cells and cells of the intestinal wall, thus acting as a kind of second gut barrier. They also contribute to the repair of the intestinal mucosa and influence the maturation of stem cells in the digestive tract.

Starting point for new treatments

Several newly identified risk genes affect the function of these mesenchymal cells in the intestines of Crohn’s disease patients—and thus could contribute to chronic inflammation. “These code variants associated with Crohn’s disease suggest that disruption of these finely balanced cellular processes, which are important for physiological homeostasis, contribute to susceptibility to Crohn’s disease,” the researchers say.

The new findings could also open up new possibilities for effectively treating IBD – for example with active ingredients that specifically target mesenchymal cells and their functions. “These genes, which have not yet been observed in previous genome studies, will lead to new avenues for treatment modalities,” says co-author Stefan Schreiber of Kiel University. (Natural Genetics, 2022; Two: 10.1038/s41588-022-01156-2)

Source: Group of Excellence in Precision Medicine for Chronic Inflammatory Diseases

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