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An international consortium of researchers has identified genetic variants in 10 genes that elevate 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 of MIT and Harvard, the study is the largest to date to focus on rare variants associated with Crohn’s disease and is published today (29 August) in Nature Genetics. These discoveries highlight the causal role of mesenchymal cells in intestinal inflammation, methotrexate 20 years helping to zero in 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 characterised by chronic inflammation of the gastrointestinal tract. The causes of the disease are poorly understood, but it is believed to be triggered by a hyperactive immune response against gut bacteria in genetically susceptible individuals. Though drugs are available that improve symptoms for many patients, there is no cure and relapsing bouts of severe illness are common.
With a few rare exceptions, there is no single genetic cause of CD. Environment, diet and genetic variation collectively shape an individual’s risk of disease. Previous genome-wide association studies (GWAS) have identified around 250 regions of the genome that influence an individual’s susceptibility to CD. Unfortunately, GWAS studies are somewhat restricted to testing sites in the human genome that frequently vary between individuals.
In this study, researchers at the Wellcome Sanger Institute and the Broad Institute set out to identify rare genetic variants within protein-coding genes that are associated with Crohn’s disease susceptibility. They performed exome sequencing1 on around 30,000 patients with Crohn’s and compared these to exome sequences from around 80,000 individuals without 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 a type of stem cell in the gut called mesenchymal cells2, suggesting that disruption of these cells contributes to the initiation and maintenance of intestinal inflammation.
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