By mapping the genetic basis, researchers at the University of California’s San Diego School of Medicine have identified a predictive causal role for certain cell types in type 1 diabetes, which affects more than 1.6 million Americans.
The results will be published in the online edition of Nature on May 19, 2021.
Type 1 diabetes is a complex autoimmune disease characterized by the deterioration and loss of insulin-producing pancreatic beta cells and the subsequent hyperglycemia (high blood sugar) that damages the body and can cause other serious health problems such as heart disease and vision loss . Type 1 is less common than type 2 diabetes, but its prevalence is increasing. At the U.S. Centers for Disease Control and Prevention, 5 million Americans will have type 1 diabetes by 2050. There is currently no cure, just disease management.
The mechanisms of type 1 diabetes, including the triggering of autoimmunity, are poorly understood. Because it has a strong genetic component, numerous genome-wide association studies (GWAS) have been conducted in recent years, in which researchers compare entire genomes of people with the same disease or condition and look for differences in the genetic code with which they may be associated Disease or condition.
In the case of type 1 diabetes, identified risk variants were largely found in the non-coding regions of the genome. In the nature study, senior author Kyle Gaulton, PhD, an assistant professor in the Department of Pediatrics at the University of San Diego Medical School, and colleagues integrated GWAS data into epigenomic maps of cell types in peripheral blood and pancreas. Epigenomic mapping describes how and when genes in cells are switched on and off and thus determines the production of proteins that are important for certain cell functions.
In particular, the researchers conducted the largest GWAS to date for type 1 diabetes, analyzing 520,580 genome samples to identify 69 new association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreatic and peripheral blood cell types.
“By combining these two methods, we were able to identify cell-type-specific functions of disease variants and discover a predictive causal role for exocrine pancreatic cells in type 1 diabetes, which we were able to validate experimentally,” said Gaulton.
Pancreatic exocrine cells produce enzymes that are secreted into the small intestine, where they help digest food.
The co-author Dr. Maike Sander, a professor in the Pediatrics and Cellular and Molecular Medicine Departments at UC San Diego School of Medicine and director of the Pediatric Diabetes Research Center, said the results are an important step in understanding the causes of type 1 diabetes. She described the work as a “landmark study”.
“The implication is that the dysfunction of exocrine cells can make a significant contribution to the disease. This study provides a genetic roadmap that we can use to determine which exocrine genes may play a role in the pathogenesis of disease. “
First author Joshua Chiou, PhD, a graduate of the Biomedical Sciences graduate program at UC San Diego added, “Understanding how type 1 diabetes develops at the cellular level is a critical step in finding treatments to match its course to reverse and ultimately prevent the disease altogether. “
Co-authors are: Ryan J. Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Rebecca Melton, Elisha Beebe, Paola Benaglio, Serina Huang, Katha Korgaonkar and Sebastian Preissl at UC San Diego; David U. Gorkin, Emory University; and Sandra Heller and Alexander Kleger, Ulm University.
Funding for this research came in part from the National Institutes of Health (grants DK112155, DK120429, DK122607 AND T32 GM008666).