Although millions of people worldwide suffer from Crohn’s disease, its causes have only been partially elucidated. A genome study is now providing new starting points. In it, researchers have identified ten new risk genes for Crohn’s disease that point to previously unknown mechanisms of development. Knowledge of these processes and the cells involved might help to find therapies for the hitherto incurable intestinal disease.
Crohn’s disease is characterized by relapsing, chronic inflammation of the gastrointestinal tract. Those affected repeatedly suffer from severe diarrhea, abdominal pain and sometimes vomiting. Drugs can alleviate the symptoms, but there is no cure so far – also because the causes of this intestinal disease have only been partially clarified. It seems clear that there is a genetic susceptibility and that the intestinal barrier and the mucous membranes of the digestive tract are pathologically altered in those affected.
Earlier genome-wide association studies (GWAS) have already identified many genomic regions that are altered in Crohn’s patients. However, the functions of these gene variants are only known in a few cases.
Ten risk genes, six of which are completely new
That’s why Aleksejs Sazonovs from the Wellcome Sanger Institute in England and his colleagues have now looked 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 subjects. For the study, the international research team analyzed samples from 30,000 patients from 35 medical centers worldwide and 80,000 control persons.
The result: “We have identified genetic variants in ten genes that increase susceptibility to Crohn’s disease,” reports co-author Andre Franke from the University of Kiel. “Changes in six genes were identified in regions that had not previously been associated with Crohn’s disease.” The four remaining genes are in regions for which the GWAS studies have already shown a connection with an increased risk of Crohn’s disease had.
Targeting mesenchymal cells
What is interesting, however, are the functions of the newly identified risk genes. Because they provide clues to a previously unknown development mechanism. “Many of the newly identified genes appear to be linked to the role of mesenchymal cells in the physiological balance of the digestive tract,” the scientists explain.
These cells and progenitor cells, which are part of the 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 in the intestine interact closely with immune cells and the cells of the intestinal wall and thus act as a kind of second intestinal 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 therapies
Several newly identified risk genes influence the function of these mesenchymal cells in the intestines of Crohn’s disease patients – and might thus contribute to the chronic inflammation. “These code variants associated with Crohn’s disease indicate that a disruption of these finely balanced cellular processes, which are important for the physiological balance, contribute to the susceptibility to Crohn’s disease,” the researchers state.
The new findings might also open up new possibilities for treating the inflammatory bowel disease effectively – for example with active ingredients that specifically target the mesenchymal cells and their functions. “These genes, which have not yet been noticed in previous genome studies, will result in new approaches for therapy methods,” says co-author Stefan Schreiber from the University of Kiel. (Nature Genetics, 2022; two: 10.1038/s41588-022-01156-2)
Source: Cluster of Excellence Precision Medicine for Chronic Inflammatory Diseases