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

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), aresignificant causes of morbidity with recent estimates suggesting there are more than 3 millionAmericans with IBD with very significant financial burden to the US economy. The world iscurrently 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) whichis most highly expressed in the gut. Our preliminary data suggests that expression of this receptoris influenced by age and obesity as well as in IBD. Differing patterns suggest differences bydisease location. Interestingly our preliminary data suggest that anti-cytokine therapy alters ACE2expression in inflamed tissue. We propose to study the overlap between these 2 conditions usinga large-scale and comprehensive genetic approach. We will study genetic variants in ACE2 andrelated genes for their effect on IBD susceptibility and disease progression as well as responseto therapy. We will study, in depth, large numbers of gene expression samples from IBD cases toinvestigate this overlap further. We will use a newer technology called single cell RNAseq todetermine which cells are leading to the changes in gene expression that we have seen with ourinitial studies. We will also use a statistical approach called Mendelian Randomization (which canbe viewed as nature's equivalent of a randomized study) to determine whether the therapies usedin IBD are likely to be beneficial or harmful in COVID-19 infection. We will use these data toidentify subjects in whom to generate pluripotent stem cells for functional work. For the functionalstudies we will use gut organoids and the IPSCs to test the effect of cytokines that reflect thedifferent inflammatory states that we have observed (ageing, obesity, ileal inflammation, colonicinflammation) 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 intothe molecular overlap of IBD and COVID-19 and what are the likely effects of anti-cytokine andother treatments used in IBD likely to be in COVID-19.