Genetics and Pathogenesis of Inflammatory Bowel Disease

Abstract

We are currently in an exciting time when our understanding of genetic underpinnings of inflammatory bowel disease (IBD) has undergone a revolution, based in large part on novel genotyping and sequencing technologies. With >160 susceptible loci identified for IBD, the goal is now to understand at a fundamental level the function of these susceptibility alleles. Determining the clinical relevance of how these susceptible genes shape the development of IBD is also a high priority. The main challenge is to understand how the environment and microbiome play a role in triggering disease in genetically susceptible individuals, as the interactions may be complex. To advance the field, novel in vitro and mouse models that are designed to interrogate complex genetics and functionally test hypotheses are needed. Ultimately, the goal of genetics studies will be to translate genetics to patients with IBD and improve their care.

Keywords: Crohn's disease; causative variants; genome-wide association study; ulcerative colitis.

Figure 1

The characteristics of different study designs and methodology of IBD genetic studies. Familial studies represent a past approach that identified a few specific targets (e.g. NOD2). Currently GWAS with fine mapping are able to identify greater number of loci; however, not all of these loci have defined gene targets. Currently whole exome and whole genome sequencing have the potential to specifically defined more genetic targets.

Figure 2

Translational functional studies based on the genetic studies of loss of function genes (i.e., VEO-IBD) can lead to identification of potential therapeutic targets. Due to the severity of the mutations, approaches using knock-out models, both in mice and cell culture, are well poised to develop systems to discover pathways targeted by these mutations as well as environmental triggers. This approach can potentially lead to novel therapeutic targets.

Figure 3

Hypothetical thresholds for genetic and environmental factors required to trigger IBD. The three scenarios include (A) environmental factors are dominant and requires less genetic risk factors (similar to an infectious disease model); (B) genetic factors are dominant (e.g. VEO-IBD), which likely requires less environmental dosage; and (C) ‘medium’ dosage of genetic and environmental factors, similar to other autoimmune disorders.

Figure 4

Different combinations of genetic and environmental factors may contribute to development of IBD in different ethnic populations. Caucasian and Asian populations appear to have some shared genetic risk factors, while others are distinct. What remains to be seen is whether the distinct genetic factors would affect common pathways. The other unknown issue is the role of environmental factors for each ethnic group.