Familial Inflammatory Bowel Disease Early Risk

The familial nature of IBD has long been identified. Observational studies have highlighted a positive family history of IBD as a major risk factor for developing IBD, with particularly high risk among first-degree relatives (FDRs) of patients with Crohn's disease (CD). Importantly, an additive risk increment of CD onset appears with each additional affected FDR. Therefore, individuals within families with multiple affected members, also known as multiplex families, harbor notably high risk of developing CD. Healthy individuals from multiplex families have been shown to have a higher number of risk alleles in IBD-associated genes compared with healthy individuals from the general population, with the mean number of risk alleles increasing alongside increasing numbers of affected FDRs. However, none of the genetic markers could discriminate between individuals from single-case families (so-called simplex families) and individuals from multiplex families. Thus, genetics is unlikely to represent the sole factor explaining the increased risk, raising the question of factors driving the increased risk of CD in multiplex families.

As IBD involves pathological immune responses, detailed study of disease immunology is central to understanding pathogenesis and progression. Sc-RNAseq and other novel immunological techniques provide the capability to interrogate individual cellular transcripts to determine pathogenic pathways, even within rare cellular subpopulations previously inaccessible using conventional techniques and bulk RNA-seq. The novelty of single-cell technologies compared with previous technologies such as bulk sequencing lies in the ability to detect rare subsets of cells potentially representing aberrant drivers of disease. Available single-cell omic technologies are described in a research paper. The inherent advantage of single-cell techniques has led to continued popularity in IBD research 8-22.

Previous work from the research group has shown that sc-RNAseq can detect changes in pediatric IBD gut tissue from dissociated tissue biopsies. The proposed study will use immunological assays, including single-cell omics, to investigate risk factors associated with development of IBD among family members of patients with already diagnosed IBD.

Inclusion criteria

• Asymptomatic first degree relative (FDR) (siblings or offspring) of patients with CD or UC aged between 0 and 55 years.

Exclusion criteria

• Nonviable neonates and uncertain viability neonates
• Antibiotic treatment within 3 months prior to recruitment
• Individuals with the presence of a known diagnosis of IBD, or symptoms suggestive of IBD
• Not within the age range of 0-55 years