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Exome sequencing study identifies new genes and variants involved in Crohn’s disease

Written by Miyako Rogers, Science Writer

A new study published in Nature uses large-scale exome sequencing to identify new genes and variants involved in Crohn’s disease. This study has identified 10 new genes which contribute to the pathogenesis and susceptibility of Crohn’s and implicated mesenchymal stem cells in the development and maintenance of the immune system in the gut.

The advantages of exome sequencing

Genome-wide association studies (GWAS) are used extensively in research, scanning the entire genome to identify small variations such as single nucleotide polymorphisms. While GWAS has identified hundreds of variants associated with Crohn’s disease, many GWAS hits do not necessarily implicate functional variants and can miss rarer coding variants, particularly in complex diseases such as Crohn’s.

In this study, researchers performed large-scale exome sequencing of 30,000 patients with Crohn’s and 80,000 controls. This approach allowed them to better define functional variants that can either give rise to actionable therapeutic targets and/or better elucidate pathological processes. The researchers identified 10 new variants, which reaffirmed the role of innate and adaptive immune cells in the pathogenesis of Crohn’s, but also uncovered the emerging role of mesenchymal stem cells in the development and regulation of inflammation in the gut.

Mesenchymal stem cells – A new target

Of the 10 identified genes, genes such as Dok2, TAGAP and IL10RA have been well defined and shown to be involved in the regulation of the immune system. TAGAP, a very rare variant, actually decreased the likelihood of developing the disease. This protective mutation could potentially give rise to therapeutic targets, and drugs mimicking the mutation may protect at-risk individuals from disease.

Figure 1 ¦ Illustration of inflamed mucosa showing the mesenchymal-related genes with newly identified mutations in blue, and proposed treatment strategies to target implicated pathways in red.

Other genes identified, including PDLIM5, HGFAC, PTAFR (PAF-R) and CCR7, highlighted the role of mesenchymal stem cells in intestinal inflammation and Crohn’s disease (Figure 1). PDLIM5 is a known regulator of SMAD3, which is involved in pathways in repair of the epithelium after tissue damage, potentially causing breakdown of the gut wall and inflammation. PTAFR is expressed in intestinal epithelial cells during repair processes, but prolonged exposure to PTFAR has been shown to dissolve cell junctions and enhance the permeability of the gut wall as well. SDF2L1 is expressed by Paneth cells, which are highly specialized secretory epithelial cells in the small intestines and is expressed in response to inflammation and ER stress. HGFAC releases HGF, which plays a role in maintaining mesenchymal stem cells, and CCR7 in dendritic cells, macrophages, and T cells also exacerbates inflammatory response.

Future directions

The team behind this study is already working on the next steps. Dr Carl Anderson, a co-author of this study said, “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.” Moreover, this method of exome sequencing to complement GWAS data could help identify new variants in other diseases.