Integration of genomic variation, ileal transcriptomics and longitudinal clinical data in paediatric inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting condition characterised by intestinal inflammation. IBD is considered a complex condition, arising from interaction between host genetic susceptibility, immune dysregulation and environmental stimuli in the form of intestinal bacteria. Paediatric onset disease is heterogenous and patients often follow an
unpredictable severe course requiring immunosuppression, biological therapy or surgery. Utilising multi‐omic and clinical data to predict disease course and complicated phenotypes, such as stricturing and fistulating disease, has the potential to provide a route to personalised therapy and improved patient outcomes.

This thesis describes the integration of genomic, targeted terminal ileal transcriptomics and longitudinal clinical data in paediatric patients with IBD. These chapters utilise a cohort of 96 individuals with intestinal biopsies including treatment naïve patients, established disease patients and control recruited during this PhD, alongside data derived from 501 patients with
whole exome sequencing. This thesis identifies novel groupings of patients determined by blood results at diagnosis. We identify a precise molecular diagnosis in 8% of patients through interrogation of variation in monogenic IBD genes, and directly link monogenic NOD2‐disease to a stricturing phenotype. Utilising the whole gene deleteriousness score, GenePy, we provide evidence for a digenic risk of development of fistulating disease in small subset of patients with high burden of variation in NCF4 and NOD2, or in the NOX4 NAPDH complex. Through targeted autoimmune transcriptomic analysis of terminal ileal biopsies we identify an upregulation of IL17 and NOD‐signalling genes in treatment naïve Crohn’s disease patients. Through single cell
sequencing of two individuals we determine a small population of specialised ileal epithelial cells driving the IL17‐signalling signature. Finally, through integration of exome and transcriptomic data we identify variation across the NOD‐signalling pathway, including in NOD2, ATG16L1 and the TAK1‐TAB complex that directly impacts on ileal transcription, leading to an overall
hypoinflammatory response.

It is increasingly clear that IBD pathogenesis is private to an individual, or a cluster of individuals. Whilst activated inflammatory pathways demonstrate commonality, the underlying cause of disease may relate to deleterious variation in many genes across implicated pathways. This genetic variation leads to an inability to clear bacteria, resulting in chronic activated inflammation through alternative immune pathways. Genetic stratification also provides the ability to predict phenotypes. The next step is translating these findings into clinical practice.

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Identifiers

ORCID for Sarah Ennis: orcid.org/0000-0003-2648-0869

ORCID for David Cleary: orcid.org/0000-0003-4533-0700

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