The Genetics of IBD

Crohn’s disease was named for Mount Sinai physician Burrill B. Crohn, MD. Dr. Crohn and colleagues first reported their findings in 1932, but genetic studies for both Crohn’s Disease and Ulcerative Colitis were not commissioned until 1997. One of the first Cohn’s Disease related susceptibility locus on chromosome 16 was discovered by Dr. Cho, who later demonstrated that a frameshift mutation of NOD2 gene on chromosome 16 was associated with the susceptibility to Crohn’s Disease. These studies confirmed the idea that Inflammatory Bowel Disease (IBD) has a strong genetic component.

With progress on the human genome project, in 2006, about 6000 Crohn’s Disease and Ulcerative Colitis patients’ genomes were sequenced. The results further supported the crucial role of genetics in these diseases. Moreover, Crohn’s Disease and Ulcerative Colitis also tend to run in families. A positive family history increases risk of IBD about 5-15 fold. IBD is more common in certain ethnic groups, especially people of Central and Eastern European Jewish descent. To date, over 163 genetic regions associated with IBD have been identified, but their functions are mostly unknown. In these 163 gene regions, there is a striking overlap between IBD and mycobacterial susceptibility, which suggests the cross-talk between genetics, microbes, and immune response.

Our lab is currently working on further identifying rare disease associated variants in the Ashkenazi Jewish population, by exome chip technology as well as the biological function of those identified genes. We are also expanding our horizons to examine the function of lipid mediators and their related cytokines in innate immune cells, and the full transcriptome of enteroids, the intestinal epithelial stem cells. By dissecting the relationship between IBD genetics, immune response, and microbes, we increase our chances at developing treatments which will  block pro-inflammatory proteins, inflammatory pathways, or immune cell entry in the intestine.

The Environmental Factors of IBD

Although a family history of IBD increases the risk of getting the diseases, the genetic components alone do not explain why certain individuals are more prone to develop IBD.  For example, in some instances, with identical twins who have the same genetic background, one may get IBD, and the other may not.   These cases suggest that there are additional factors besides the genetic background, such as environmental influences, that play an important role in the development of IBD.

Currently, microbes are the main environmental factor associated with the risk of IBD. Several population studies establish the possible link microbes have to the prevalence of IBD.  For instance, based on the data from 1890 to 1900 in New York and London, fewer people from Ashkenazi Jewish populations died than those from other ethnic groups from mycobacterial infections yet  Ashkenazi Jewish populations are more susceptible to IBD.   In addition, human genetics studies have shown that IBD associated genes affect how we interact with microbes such as the first identified Crohn’s Disease gene-NOD2, a common bacterial sensor. Recent work by our lab has demonstrated that there is a striking overlap between IBD and mycobacterial susceptibility genes. These studies support the hypothesis that there is a strong link between IBD susceptibility and microbes.

It is unclear which microbes cause IBD. So far, yeasts, viruses, and gut bacteria have been implicated as IBD-associated microbes. Clinically, Crohn’s patients have anti-Saccharomyces cerevisiae mannan (ASCA), which are the components of yeast cell wall antibodies, in their serum (ASCA) and are often used as serological makers. Mice studies reveal that noravirus and enterovirus may trigger symptoms similar to those of IBD.  More recently, by taking the high throughput sequencing approach, several groups have shown that IBD patients have dramatic changes in their gut bacteria profiles. Normally, IBD patients have reduced gut bacteria diversity. In newly onset Crohn’s Disease children, an increase in EnterobacteriaceaePasteurellacaeaVeillonellaceae, and Fusobacteriaceae, and a decrease in ErysipelotrichalesBacteroidales, and Clostridiales have been observed.  Recently, another group demonstrated that IgA-bound gut bacteria are the major drivers for IBD inflammation. IgA is the major gut-protective antibody.  All above findings suggest that those microbes are likely the environmental factors that drive IBD pathogenesis.

With the combination of human genetics, “omics,” and molecular & cellular biology approaches, our lab will investigate how hosts (humans) interact with gut microbes and how this interaction may lead to IBD susceptibility and/or maintain IBD pathogenesis.