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Shedding Light on the Functional Genetic Architecture of Inflammatory Bowel Disease

Recent findings have uncovered two genetic variants that increase the risk for inflammatory bowel disease (IBD) and also provided clues to their functional impacts, including interactions with the immune system and gut microbes. IBD is the general term for the diseases, including Crohn’s disease and ulcerative colitis, that are characterized by chronic inflammation in the gut. This inflammation leads to recurring abdominal cramps, bleeding, and diarrhea. Effective treatments for IBD have been elusive, largely because the disease is a result of complicated interactions between multiple genetic and environmental factors, including an improper response to bacteria inhabiting the gut. To discover the genetic underpinnings of IBD, the NIDDK’s IBD Genetics Consortium has enrolled thousands of patients and identified more than 200 regions of the human genome that are associated with risk of Crohn’s disease or ulcerative colitis, yielding important new insights into the nature of IBD. Building upon these important first steps, the Consortium is now working together with international colleagues to identify and characterize specific genetic variants that are involved in IBD susceptibility. This is important because even if a genetic variant is rare, its linkage to IBD could give insight into how the disease develops. For example, several variants identified thus far appear to affect the immune system, which in turn could affect the gut’s reaction to resident bacteria.

One group of scientists, including members of the NIDDK IBD Genetics Consortium, sought to discover new genetic variants that would have a strong effect on the likelihood of developing Crohn’s disease. They focused on the Ashkenazi Jewish population, which has a higher prevalence of the disease than non-Jewish people of European ancestry. Analyzing DNA from a population of men and women of Ashkenazi Jewish descent—approximately 1,500 with Crohn’s disease and 2,600 without the disease—the researchers found a rare variant of a gene called CSF2RB that was more common in the people with the disease. This finding was validated by examining the DNA of another Ashkenazi Jewish study population with approximately 1,500 people with Crohn’s disease and 7,000 healthy people. When this variant was introduced into human cells grown in the laboratory, it weakened the activation of a signaling pathway critical for restraining the immune response. Immune cells from Ashkenazi Jewish people with this variant had similar defects in this signaling pathway. These results suggest that this variant may confer IBD risk by failing to repress certain immune reactions.

Another research team with ties to the NIDDK IBD Genetics Consortium and other international consortia combed the genomes of over 10,000 people, both women and men, of non-Jewish European ancestry with IBD (Crohn’s disease or ulcerative colitis) and over 5,000 people without IBD to find new genetic variants that are associated with the disease. They found a variant in a gene called SLC39A8 that was more common in people with Crohn’s disease compared to people without this disease (controls). When activated, the SLC39A8 gene produces a protein within cells that transports zinc. Interestingly, this particular genetic variant has also been implicated in other aspects of health, including obesity. Knowing that both IBD and obesity are associated with changes in gut bacteria, and that zinc metabolism relates to immune function, the researchers thought that this variant may somehow be affecting the gut microbiome. Examining the microbiomes of over 300 people from another study, the scientists found that the SLC39A8 variant was associated with an altered gut microbiome in both the controls and the people with IBD. These results point to differences in the gut microbiome—driven by variations in the human genome—that could eventually contribute to IBD or obesity.

Uncovering the roles of these genetic variants in IBD offers targets for developing potential new treatments and provides remarkable insight into how the disease develops. It also identifies genetic markers that could be used for screening to help individuals seek treatment before symptoms become severe.