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Crohn’s disease (Crohn’s disease, CD) , also called inflammatory bowel disease (inflammatory bowel disease, IBD) is an immune-related intestinal inflammatory disease caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals. The exact immune issues of Crohn's disease are not yet clear [1] . Genome-wide association studies (Genome-wide association studies, GWASs) successfully discovered more than 200 loci related to the risk of the disease, but most of the discovered loci were not related to genes or sequences with regulatory functions. Only a small subset of loci map to coding regions that provide clues to the pathogenesis of Crohn's disease.
In order to improve the results of previous GWASs and better define biological targets for Crohn's disease, August 29, 2022, from MIT, Harvard University and University of Helsinki and many others Researchers from the research center published a paper titled Large-scale sequencing identifies multiple genes and in the journal Nature Genetics rare variants associated with Crohn’s disease Susceptibility's article jointly analyzed sequencing data from more than 30,000 Crohn's disease patients and 80,000 control subjects. discovered 10 genes related to the onset of common CD. We In addition to the central role of innate and adaptive immune cells and autophagy in the pathogenesis of CD, these newly discovered genes related to CD pathogenesis suggest the role of mesenchymal cells in the development and maintenance of intestinal inflammation. Provides an important theoretical basis for developing treatments .
In this article, in order to further reveal the GWAS loci, the authors used Crohn's disease case and control specimens from more than 35 centers of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) Large-scale exome sequencing was performed. The primary analysis included sequencing of the exon set of 18,816 CD cases from 35 IBD studies and 13,412 non-IBD control samples from the same studies. The data were generated using two different exome capture platforms: Nextera (Illumina) and Twist (Twist Biosciences) . After parallel calling and quality control of data from the two exome capture platforms, the authors analyzed variables using log mixed models and standard inverse variance weighted meta-analysis. The significance threshold within the study range is 3 × 10−7. It was found that exonic variants are significantly associated with IBD, and the most significantly associated variant (P 10−10) is a previously known CD variant (or a linkage disequilibrium variant associated with it), indicating the authors' analysis The process eliminates highly relevant false positives to .
In order to identify new loci and independent exon association signals of known loci that have not been involved in Crohn's disease in previous studies, the authors analyzed 45 exon significant variants and previously reported IBD GWAS targets and found Some new CD genes contribute to a series of known signaling pathways , including autophagy, inflammatory response functions, etc., and many new genes related to mesenchymal cells (mesenchymal cells, MCs) have also been discovered. has been implicated in its role in intestinal homeostasis, a pathway that has not been previously implicated in genetic studies.
Schematic diagram of inflamed mucosa, illustrating a series of newly discovered mesenchyme-related genes and their mechanisms of action
Overall, in this article, the authors demonstrate that large-scale exome sequencing can complement previous GWASs study, New genes discovered in this study further confirm the central role of innate and adaptive immune cells and autophagy in Crohn's disease and point to a link between Crohn's disease and mesenchymal cells The association provides additional theoretical basis for the development of new drugs and the treatment of Crohn's disease.. In addition, the authors anticipate that ongoing further sequencing work in ulcerative colitis will be completed next year, allowing for a more comprehensive study of ulcerative colitis.
reference information and original text link
1. https://en.wikipedia.org/wiki/Crohn%27s_disease
2. https://doi.org/10.1038/s41588-022-01156-2
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