Landmark study identifies cellular culprit for Type 1 diabetes

Landmark study identifies cellular culprit for Type 1 diabetes
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A landmark study has mapped the genetic underpinning for Type 1 diabetes, enabling the identification of a predictive causal role for specific cell types in Type 1 diabetes.

Researchers at the University of California San Diego School of Medicine have identified cell type-specific functions of disease variants, uncovering a predictive causal role for pancreatic exocrine cells in Type 1 diabetes.

The complex autoimmune condition is characterised by the impairment and loss of insulin-producing pancreatic beta cells and hyperglycemia, which can cause problems such as heart disease and vision loss. Currently, there is no cure for Type 1 diabetes, only management of the condition.

The findings, which the researchers say represent a major leap in understanding the causes of Type 1 diabetes, have been published in the journal Nature.

Disease pathogenesis

Type 1 diabetes is poorly understood, including how autoimmunity is triggered. As the condition has a strong genetic component, a number of studies have been conducted in which researchers compare whole genomes of persons with the same disease or condition, looking for differences in the genetic code that may be associated with that condition. At-risk variants for Type 1 diabetes have largely been found in the non-coding regions of the genome.

In this study, senior author Kyle Gaulton, PhD, an assistant professor in the Department of Pediatrics at UC San Diego School of Medicine, and colleagues, integrated genome wide association studies (GWAS) data with epigenomic maps of cell types in peripheral blood and the pancreas, which maps how and when genes are turned on and off in cells, determining the production of proteins vital to specific cellular functions.

Specifically, researchers performed the largest-to-date GWAS of type 1 diabetes, analysing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.

Gaulton said: “By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally.”

Pancreatic exocrine cells produce enzymes secreted into the small intestine, where they help digest food.

Co-author Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Pediatric Diabetes Research Center, said: “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.”

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