By harnessing various genetic tools, researchers have identified a predictive causal role for specific cell types in type 1 diabetes.
Type 1 diabetes
Type 1 diabetes (T1D) is a complex autoimmune disease characterised by the loss of insulin-producing pancreatic beta cells. It is also associated with other serious health problems including heart disease and vision loss. Approximately 400,000 people in the UK and 1.6 million Americans are affected by T1D. However, the triggers of autoimmunity and disease remain poorly understood.
T1D has a strong genetic component. Through genome-wide association studies (GWAS) several genetic risk variants have been identified. The most prominent genetic risk factor is the major histocompatibility complex (MHC) locus. Risk variants for T1D are also primarily non-coding. However, the mechanisms of action of T1D risk loci remain unclear. Translating these variants into mechanistic insights requires detailed maps of gene regulation within the disease-relevant cell types.
Genetics and single-cell epigenomics
In this study, published in Nature, researchers integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas. The researchers performed the largest GWAS to-date of T1D diabetes, analysing 520,580 samples and subsequently identifying 69 novel association signals. They then mapped 448,142 cis-regulatory elements (cCREs) in the pancreas and peripheral blood cell types using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC–seq).
The team found that risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including pancreatic exocrine cells. Pancreatic exocrine cells produce enzymes that get secreted into the small intestine for digestion.
Co-author, Maike Sander, stated:
“The implication is that exocrine cell dysfunction might be a major contributor to disease. This study provides a genetic roadmap from which we can determine which exocrine genes may have a role in disease pathogenesis.”
Overall, these findings support a role for pancreatic exocrine cells in the pathogenesis of T1D. This study also emphasises the power of combining GWAS data with single-cell epigenomics data for understanding the cellular origins of complex disease.
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