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

NIH Pandemic-Era Grants

Pandemic Era Grants

2020

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Principal Investigator: Dermot Patrick McGovern
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2020
Award: $346,893
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

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.

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