Gene variants reveal susceptibility to Crohn's disease
Tuesday August 30th 2022
Variants in ten genes that increase an individual’s susceptibility to Crohn’s disease have been identified for the first time, thanks the largest study to date on the subject, it was announced last night.
An international team led by researchers from the Wellcome Sanger Institute, Cambridge, UK, and the Broad Institute of MIT and Harvard, USA, highlight the causal role of mesenchymal cells in intestinal inflammation which help to pinpoint the genetic roots of inflammatory bowel disease.
The findings will go on to provide better data with which to develop the next generation of treatments, the researchers say.
Previous genome-wide association studies (GWAS) have identified about 250 regions of the genome that influence an individual’s susceptibility to Crohn’s disease, but these have been restricted to sites in the human genome that frequently vary between individuals.
In this study, which is published in the latest edition of Nature Genetics, the research team wanted to identify rare genetic variants within protein-coding genes associated with Crohn’s disease susceptibility.
They performed exome sequencing on about 30,000 patients with Crohn’s and compared these to exome sequences from about 80,000 individuals who do not have the condition.
This identified genetic variation within six genes in regions of the genome that had not been previously connected to Crohn’s disease.
Several of these genes are known to play important roles in mesenchymal cells, which the authors say suggests that disruption of these cells contributes to the initiation and maintenance of intestinal inflammation.
First study author Dr Aleksejs Sazonovs, of the Wellcome Sanger Institute, said: “Most humans will have some of the genetic variants that increase susceptibility to inflammatory bowel disease because they’re so common.
“These common variants may increase a person’s risk by 10%, for example, but this increased risk doesn’t necessarily lead to disease. But some rare variants can make someone four or five times more likely to develop inflammatory bowel disease, so it’s especially important to locate these and understand the biological processes they disrupt.”
The remaining four identified genes are found within regions of the genome previously associated with inflammatory bowel disease (IBD) via GWAS.
One rare variant, in the TAGAP gene, decreases a person’s likelihood of developing the disease and researchers say these protective mutations suggest a certain gene may be disabled without adverse side effects in people.
Drugs that mimic the mutation, such as by disabling the protein the gene encodes, could confer some of the same protection in patients.
The next step will be to extend the approach to ulcerative colitis and increase the scale of sampling, in the hope of locating all variants and genes involved in IBD.
Senior study author Dr Carl Anderson, from the Wellcome Sanger Institute, said: “To have the statistical power to spot the rare variants that are driving disease, these studies require tens of thousands of individuals.
“We need international collaborative teams, such as the International IBD Genetics Consortium, to bring together sufficient DNA samples to make this possible. We’ve already begun working on our next study, which will use exome sequence data from more than 650,000 individuals and give us unprecedented ability to derive insights into the aberrant biology underpinning inflammatory bowel disease.”
Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nature Genetics 29 August 2022
Tags: Gastroenterology | Genetics | North America | UK News
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