Researchers at Cincinnati Children’s Hospital and Imperial College London have uncovered new information regarding how genetic risk factors trigger autoimmune conditions. The study focuses on type 3 innate lymphoid cells, known as ILC3s, which reside in the gut and airway tissues. These cells play a critical role in managing inflammation and maintaining barrier integrity, but their rarity has historically made them difficult to analyze using standard genetic mapping techniques.
To overcome these limitations, the team applied a low-input, high-resolution approach called Promoter Capture Hi-C. This method allowed the investigators to map long-distance DNA interactions in primary human cells. By combining these maps with existing genome-wide association study data, they identified connections between specific risk variants and the genes they regulate. The study successfully linked Crohn’s disease risk variants to over 100 candidate genes, providing a clearer picture of the mechanisms involved in these disorders.
One significant finding involves the gene CLN3. While primarily recognized for its role in Batten disease, this research suggests it may also influence inflammatory activity in ILC3s. Experimental testing indicated that modulating CLN3 expression changes how these cells respond to cytokine stimulation. Although this does not confirm a causal relationship in Crohn’s disease, it highlights a functional role for the gene within the immune system.
This research provides a catalog of risk genes across six autoimmune conditions. By moving beyond the assumption that risk variants only act on their nearest neighbor, the team has created a more precise framework for understanding how genome folding affects disease. Future work aims to clarify the specific pathways involved and apply this mapping strategy to other rare cell populations that have remained out of reach for traditional genomic studies.