Understanding inflammatory bowel disease via immunogenetics

Abstract

The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.

The epigenetics of PBC: The link between genetic susceptibility and environment

“…Besides that, some mechanisms remain largely unknown, such as causal nucleotide changes, rare genetic variants or the missing heritability sequencing [19][20][21]. Indeed, the use of GWAS have been very disappointing, i.e., it is likely that there are loci that have not been identified due to a lack of statistical significance; this is true not only of PBC, but also for a variety of other AIDs, many of which have been recently reviewed [22][23][24][25][26][27][28][29][30][31][32][33]. As a consequence, progress towards understanding disease mechanisms has been limited by difficulties in assigning a molecular function to the vast majority of GWAS hits that do not affect protein-coding sequences.…”

Role of peripheral dopaminergic system in the pathogenesis of experimental colitis in rats

“…The exact cause of IBD has yet not been fully elucidated, although accessible data suggests that IBD results from adverse interactions between susceptibility genes, microbiome, the environment, and the immune system which can cause an excessive and abnormal immune response against host microbiome in genetically susceptible individuals [28]. Most recently described IBD susceptibility genes are linked to host immune system including epithelial barrier function, host defence mechanisms against pathogens as well as autophagy, innate and adaptive immune response [29].…”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…Genetics play a role in disease susceptibility [113], and in a large Danish twin cohort, 44% of patients with CD are positive for at least one mutant allele of NOD2/CARD15 compared to 2% of UC patients (p < 0.001) and 19% of healthy twins (p ¼ 0.02 [114]. In concordant twin pairs, localization of the disease is identical in 11/17 MZ concordant pairs at diagnosis (p ¼ 0.008) and in 11/16 pairs after 10 years (p ¼ 0.02), moreover, MZ UC twins were concordant (within 5 years) for age at diagnosis (6/9 pairs; p < 0.001) and symptomatic onset (4/9 pairs; p ¼ 0.02) but not for extent of disease at diagnosis or after 10 years [115].…”