Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases

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The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are significant causes of morbidity with recent estimates suggesting there are more than 3 million Americans with IBD with very significant financial burden to the US economy. The world is currently in the middle of a global pandemic caused by SARS-CoV2 which is the cause of COVID- 19. Preliminary studies have identified shared molecular signatures between IBD and COVID-19. Of interest is that the receptor for SARS-COV2 is angiotensin converting enzyme 2 (ACE2) which is most highly expressed in the gut. Our preliminary data suggests that expression of this receptor is influenced by age and obesity as well as in IBD. Differing patterns suggest differences by disease location. Interestingly our preliminary data suggest that anti-cytokine therapy alters ACE2 expression in inflamed tissue. We propose to study the overlap between these 2 conditions using a large-scale and comprehensive genetic approach. We will study genetic variants in ACE2 and related genes for their effect on IBD susceptibility and disease progression as well as response to therapy. We will study, in depth, large numbers of gene expression samples from IBD cases to investigate this overlap further. We will use a newer technology called single cell RNAseq to determine which cells are leading to the changes in gene expression that we have seen with our initial studies. We will also use a statistical approach called Mendelian Randomization (which can be viewed as nature’s equivalent of a randomized study) to determine whether the therapies used in IBD are likely to be beneficial or harmful in COVID-19 infection. We will use these data to identify subjects in whom to generate pluripotent stem cells for functional work. For the functional studies we will use gut organoids and the IPSCs to test the effect of cytokines that reflect the different inflammatory states that we have observed (ageing, obesity, ileal inflammation, colonic inflammation) on ACE2 expression. The results from these analyses will also help us refine our ‘big data’ approach described earlier. We anticipate that these studies will give us insights into the molecular overlap of IBD and COVID-19 and what are the likely effects of anti-cytokine and other treatments used in IBD likely to be in COVID-19.