Zeroing In on Genes Involved in Crohn’s Disease

Researchers have identified genetic variants in 10 genes that increase susceptibility to Crohn’s disease (CD), a form of inflammatory bowel disease (IBD). Some of the variants had not previously been connected to CD.

Because they’re so common, most people will have some of the genetic variants that increase susceptibility to IBD, first author Aleksejs Sazonovs, PhD, research associate at the Wellcome Sanger Institute, Hinxton, United Kingdom, says in a news release.

“These common variants may increase a person’s risk by 10%, for example, but this increased risk doesn’t necessarily lead to disease,” Sazonovs explains.

However, some rare variants can render an individual four or five times more likely to develop IBD, “so it’s especially important to locate these and understand the biological processes they disrupt,” Sazonovs adds.

The study was published online August 29 in Nature Genetics.

Causal Link to Mesenchymal Cells?

Genome-wide association studies (GWASs) of CD, and of IBD more generally, have identified more than 200 loci that contribute to disease risk.

To complement GWAS data and to better define actionable biological targets in protein-coding genes, the researchers analyzed large-scale exome sequencing data from more than 30,000 patients with CD and 80,000 control persons from more than 35 centers in the International IBD Genetics Consortium.

Their findings, they say, “directly implicate” genetic variants in 10 genes in general-onset CD, four of which lie within established CD GWAS loci.

They also implicate genetic variation in six genes in regions of the genome that had not previously been connected to CD.

Of note, say the researchers, many of these newly associated genes appear to be linked to the roles that mesenchymal cells (MCs) play in intestinal homeostasis, “a pathway not previously implicated by genetic studies.

“In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation,” they add.

The researchers note that previous studies have demonstrated that the biology of MCs is disrupted in IBD. The current findings of coding variants in these genes demonstrate that these cells and functions “causally contribute to disease susceptibility,” they write.

The association of these pathways with CD pathogenesis provides a rationale for developing therapeutic modalities that can “reestablish the balance to the mesenchymal niche, as it is believed that genetic evidence for a drug target has a measurable impact on drug development,” they add.

The researchers plan to extend this research to ulcerative colitis and to increase the scale of sampling.

“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,” Carl Anderson, PhD, senior investigator at the Wellcome Sanger Institute, says in the release.

Support for the study was funded by the National Institutes of Health, the Wellcome Trust, and the Leona M. and Harry B. Helmsley Charitable Trust. Sazonovs reports no relevant financial relationships. Anderson has received consultancy fees from Genomics PLC and BridgeBio Inc and lecture fees from GlaxoSmithKline.

Nature Gen. Published online August 29, 2022. Abstract

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