Genetic Studies Identify New Pathways in Inflammatory Bowel Disease

Mount Sinai researchers have identified attractive new therapeutic targets for inflammatory bowel disease (IBD) through an enhanced understanding of genetic risk variants that are disproportionately represented in certain ethnic populations. In two new studies led by Judy H. Cho, MD, Dean of Translational Genetics at the Icahn School of Medicine at Mount Sinai, investigators defined novel approaches for treating Crohn’s disease and ulcerative colitis (UC) that could help set new parameters for future research.

One of the studies, published in Gastroenterology, identified population-specific effects of common and rare IBD variants on disease prediction and pathophysiology. Specifically, researchers discovered several very early-onset IBD genes with high penetration in the Mount Sinai BioMe™ biobank, which is composed of nearly 30,000 individuals from a variety of ethnic backgrounds. The IBD variant with the highest penetrance was located in the gene LRBA; it was found to cause a harmful change in amino acid structure as well as reduced expression of the secondary signaling pathway CTLA-4, which may trigger autoinflammation that contributes to IBD.

“Targeting reduced CTLA-4 expression through hydroxychloroquine, a potent disease-modifying agent that has previously had some effect on IBD, could be an exciting treatment avenue,” says Dr. Cho, who is Director of The Charles Bronfman Institute for Personalized Medicine at Icahn Mount Sinai. “Hydroxychloroquine prevents the degradation of CTLA-4 and could play a meaningful role in treating ulcerative colitis and Crohn’s disease in carriers of the LRBA mutation.”

Setting the stage for the study is the fact that rare genetic variants are usually found in select populations. What’s more, those variants can be instrumental in accurately predicting genetic disease risk in individuals across diverse ancestries, and thus could favorably impact patient outcomes given the importance of early intervention and preventive measures in IBD. The research reported, however, that IBD genetic studies to date have been overwhelmingly focused on individuals of European descent, and in the future it will be important to increase the sample size of non-European IBD genome-wide association studies (GWAS) as a way to improve prediction within each population, and to gain information about variants that may be very rare.

Mount Sinai researchers learned that for every BioMe population assessed, predictive accuracy was optimized when GWAS data from European, African American, and Ashkenazi Jewish sectors were integrated. IBD prediction among African Americans was found to be the least accurate among the populations studied, possibly because of the greater genetic diversity within that ethnic segment as well as the smaller sample size of people with African ancestry in IBD association studies. “Our results highlight the need for more non-European studies, particularly in African Americans, if we’re going to improve disease risk prediction and develop more targeted therapies for all populations with IBD,” says Dr. Cho.

Role of Mast Cell Activation

As the population with the highest IBD concentration, Ashkenazi Jews factored heavily in the second Mount Sinai-led study, which again identified a potentially valuable target for IBD, this time through mechanisms of mast cell activation, particularly a class of genes known as G-protein coupled receptors (GPCRs). The research, described in Gastroenterology, hypothesized that mast cell activation might play a key role in ulcerative colitis inflammation based on recent studies showing the importance of MRGPRX2, a type of GPCR, in mast cell activation. Targeting mast cell mediators has proven highly effective in allergic and IgE-mediated diseases, including asthma.

Mount Sinai investigators found that inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, while decreased activation was observed through a genetic variant that alters MRGPRX2 functional activity and protects against developing ulcerative colitis. “Mast cells are particularly compelling cellular targets,” notes Dr. Cho, senior author of the study, “and blocking MRGPRX2 activation and protease release could be a very promising and effective approach to treating ulcerative colitis.”

To that end, an active development program is underway with outside biotechnology partners.