ESPEYB18 15. Editors’ Choice (1) (16 abstracts)
15.2. Interpreting type 1 diabetes risk with genetics and single-cell epigenomics
Joshua Chiou , Ryan J Geusz , Mei-Lin Okino , Jee Yun Han , Michael Miller , Rebecca Melton , Elisha Beebe , Paola Benaglio , Serina Huang , Katha Korgaonkar , Sandra Heller , Alexander Kleger , Sebastian Preissl , David U Gorkin , Maike Sander & Kyle J Gaulton
Nature. 2021 volume 594, 398–402https://www.nature.com/articles/s41586-021-03552-w
The authors report a large genome-wide association study (GWAS) of type 1 diabetes (T1D) in 18 942 cases and 501 638 controls, finding 92 T1D-associated genomic loci (59 known and 33 novel). Furthermore they analyse DNA chromatin patterns in pancreas and peripheral white blood cells to help identify the underlying genes. T1D-associated loci were linked to genes that are active in T cells, but also in the acinar and ductal cells of the exocrine pancreas.
As well as performing the largest GWAS for T1D to date and finding 50% more risk loci for this disease, the major novel and eventually highly informative approach here was the integration of GWAS data with single-cell epigenomics data in very specific cell types. This approach relies on the understanding that certain DNA chromatin patterns indicate whether or not a gene is expressed (active) in a specific cell or tissue type. It involved analysing data on chromatin accessibility profiles from 131,554 individual cells. It is well known that T1D is an autoimmune condition related to T cell function. So the findings here that implicate genes active in T cells, and in insulin expressing pancreatic beta cells, are confirmatory and as ‘positive controls’, they provide confidence in the novel approach.
The more unexpected finding was the involvement of several genes that are active in the acinar and ductal cells of the exocrine pancreas. For example, at the CFTR gene locus (which is mutated in cystic fibrosis), the T1D risk variant appears to reduce transcription factor binding, enhancer activity and CFTR expression in ductal cells, and increases the risks for acute and chronic pancreatitis. The authors note that the onset of T1D has been associated with exocrine pancreas abnormalities (1), and speculate that factors that increase pancreatic exocrine cell inflammation may contribute to intra-islet inflammation and immune infiltration and thus promote T1D.
Reference: 1. Virostko J et al. Pancreas volume declines during the first year after diagnosis of type 1 diabetes and exhibits altered diffusion at disease onset. Diabetes Care 42, 248–257 (2019)
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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