An international consortium of researchers has identified genetic variants in 10 genes that increase a person’s susceptibility to Crohn’s disease, a form of inflammatory bowel disease.
Led by researchers from the Wellcome Sanger Institute and the Broad Institute at MIT and Harvard, the study is the largest to date to focus on rare variants associated with Crohn’s disease and is published today (August 29). ) in Natural genetics. These findings highlight the causal role of mesenchymal cells in intestinal inflammation, helping to focus on the genetic roots of inflammatory bowel disease and providing better data with which to develop the next generation of treatments.
Crohn’s disease (CD) is a debilitating condition characterized by chronic inflammation of the gastrointestinal tract. The causes of the disease are poorly understood, but it is thought to be triggered by an overactive immune response against gut bacteria in genetically susceptible individuals. Although there are medications that improve symptoms for many patients, there is no cure and recurrent episodes of severe illness are common.
With very few exceptions, there is no single genetic cause for CD. Environment, diet, and genetic variation collectively shape an individual’s risk of disease. Previous genome-wide association studies (GWAS) have identified approximately 250 regions of the genome that influence an individual’s susceptibility to CD. Unfortunately, GWAS studies are somewhat limited to human genome test sites which frequently vary from individual to individual.
In this study, researchers from the Wellcome Sanger Institute and the Broad Institute set out to identify rare genetic variants in protein-coding genes that are associated with susceptibility to Crohn’s disease. They performed exome sequencing on about 30,000 patients with Crohn’s disease and compared them to exome sequences from about 80,000 people without the disease.
This identified genetic variation in six genes in regions of the genome that had not previously been linked to Crohn’s disease. Several of these genes are known to play important roles in a type of gut stem cells called mesenchymal cells, suggesting that disruption of these cells contributes to the initiation and maintenance of gut inflammation.
Most humans will have some of the genetic variants that increase susceptibility to inflammatory bowel disease because they are so common. These common variants can increase a person’s risk by 10%, for example, but this increased risk does not necessarily lead to disease. But some rare variants can make a person four or five times more likely to develop inflammatory bowel disease, so locating them and understanding the biological processes they disrupt is particularly important. »
Dr. Aleksejs Sazonovs, first author of the Wellcome Sanger Institute study
The remaining four genes identified by the team reside in regions of the genome previously associated with IBD via GWAS. Unfortunately, the common genetic variants that these GWAS associate with disease lie outside of protein-coding genes, making it difficult to analyze disease biology. Identifying the particular genes in these regions that underlie susceptibility to Crohn’s disease puts an end to this challenge and the biological pathways in which these genes function can now be considered for pharmaceutical interventions.
A rare variant, in the DIFFERENCE gene, decreases the likelihood that a person will develop the disease. These variants, called “protective mutations,” are of interest to researchers in part because they suggest that a certain gene can be turned off without adverse side effects in humans. Drugs that mimic the mutation, for example by turning off the protein encoded by the gene, could confer some of the same protection on patients.
Dr Mark Daly, lead author of the study from the Broad Institute of MIT and Harvard, said: “In thinking about how to develop new therapies, it is essential that we can identify the specific genetic variants that increase or decrease a person’s risk.When we discover a disease association with a genetic variant within a gene, we can begin to conduct experiments the next day to determine what the variant, gene and protein it encodes are doing to influence disease risk. A lead in converting these observations into a therapeutic hypothesis.”
The next step will be to extend the approach to ulcerative colitis and increase the sampling scale, in the hope of locating all variants and genes involved in IBD. Better data should help make drug discovery a more efficient and faster process, offering a ray of hope to those affected by the disease.
Dr Carl Anderson, lead author of the Wellcome Sanger Institute study, said: “To have the statistical power to pinpoint the rare variants that cause disease, these studies require tens of thousands of people. We need international collaborative teams, such as the International IBD Genetics Consortium, to gather enough DNA samples to make this possible. We have already started work on our next study, which will use exome sequence data from over 650,000 individuals and give us an unprecedented ability to glean insights into the aberrant biology that underlies inflammatory diseases of the body. ‘intestine.”
Welcome Trust Sanger Institute
Sazonov, A. et al. (2022) Large-scale sequencing identifies several rare genes and variants associated with susceptibility to Crohn’s disease. Natural genetics. doi.org/10.1038/s41588-022-01156-2.