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Approved Research

Genetic factors implicated in Hirschsprung associated Enterocolitis and possible association with Inflammatory Bowel Disease

Principal Investigator: Miss Francesca Rosamilia
Approved Research ID: 86487
Approval date: August 9th 2022

Lay summary

Hirschsprung disease (HSCR) is a genetic complex disease characterized by a congenital lack of innervation in the gut. HSCR associated Enterocolitis (HAEC) is a common life!threatening complication in HSCR, likely due to a gut immune system impairment. The genetics of Hirschsprung have been extensively investigated, identifying several genes variously implicated in the disorder. Since one third of HSCR patients develop HAEC, it is likely that these genes might be implicated in HAEC as well. We have recently proposed a gene that might increase HAEC risk, and we are currently identifying several other HAEC candidate genes.

HAEC share clinical inflammatory features with the Inflammatory Bowel Diseases (IBDs), and some studies have described a possible co-occurrence of HSCR and IBDs.

A genetic overlap between HSCR and IBDs is poorly investigated, and even less between HAEC and IBDs.

Neverthless, our hypothesis is that HAEC and IBDs possible co-occurrence, similar clinical presentation and inappropriate immune response supports shared genetic factors.

Through the UK Biobank, we aim to analyze the IBDs genetic data filtered by the International Classification of Diseases (ICD codes). These data will allow us to carry out a genetic association analysis between IBDs and the genes already known or suggested to be involved in HSCR and HAEC.

We will perform a genetic association analysis to investigate if specific variants are significantly more frequent in a sample of patients affected by a given disease than in the general population (not affected by that disease). The assumption is that, if a variant is implicated in a disorder, it will be present in patients with that disorder more often than in people not affected.

We thus mean to search for genetic variants implicated in HSCR and HAEC that might be implicated in IBDs as well. Every association signal, interesting variant or mutation identified through this project will be worth being replicated in subsequent studies and furtherly investigated through different strategies, in order to elucidate HAEC genetics. In particular, the hints on the involvement of immune system and inflammatory pathways already hypothesized for HAEC patients, if confirmed in the present study, might lead to specific therapeutic strategies.

The finding of genes implicated in both disorders would also help to elucidate the HAEC and IBDs pathogenic mechanisms. In this light, the improved knowledge that we aim to achieve on HAEC by the present proposal could be applied to other disorders with similar clinical characteristics such as IBDs.