IBD Genetics Initiative
We are proud to be pioneers in this area, thanks to our groundbreaking Genetics Initiative.
Experts have long known that family history plays a role in IBD, but it’s only in the past two decades that we’ve been able to pinpoint specific genes and gene-controlled pathways that determine who’s vulnerable.
Since 2012, the Genetics Initiative has been dedicated to learning which genes play a role in determining who’s susceptible to Crohn’s disease and ulcerative colitis, including how increased or decreased expression of certain genes may affect underlying pathways of these diseases, such as the strength of the intestinal barrier. Since then, the Initiative has helped identify hundreds of genes that appear to predispose someone to IBD or make them more vulnerable to frequent flares or severe disease.
Discovering the Link Between Genes and Gut Health
Foundation-funded research led to the discovery of NOD2, the first gene ever identified as relevant to Crohn’s disease. More recently, we sponsored research by Ramnik Xavier, MD, PhD, of Harvard Medical School, and Kara Lassen, PhD, formerly of the Broad Institute of MIT and Harvard, that identified how a specific genetic change may lead to a weakened intestinal barrier. They discovered that a single protein produced by the C1ORF106 gene can alter the junctions that connect the cells that form this intestinal barrier.
Our Genetics Initiative is also responsible for the discovery of a genetic variant that makes some IBD patients overproduce a protein called PAI-1 (plasminogen activator inhibitor 1). High levels of PAI-1 interfere with gut healing by blocking a protein called TPA (tissue plasminogen activator). This research, which was led by Thad Stappenbeck, MD, PhD, at the Cleveland Clinic’s Lerner Research Institute, provides a major clue as to why gut ulcers in people with IBD do not heal properly.
Dr. Stappenbeck’s team theorized that if PAI-1 could be blocked, TPA would do its job in promoting the needed tissue repair. The most exciting part is that his team has already identified, with support of the Foundation’s IBD Ventures program, a compound that appears to block PAI-1. This compound is gut-restricted, which means it remains in the gut and does not circulate in the bloodstream so side effects should be minimized. A drug development company is currently in the process of refining and testing this compound and hopes to move to clinical trials within a few years.
