Largest genetic study identifies new drug targets to treat type 1 diabetes

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Scientists have completed the largest and most diverse genetic study ever in type 1 diabetes, identifying new drug targets to treat a disease that affects 1.3 million American adults.

Several potential drugs are already in preparation. Drugs targeting 12 genes identified in the diabetes study have been tested or are being tested in clinical trials for autoimmune diseases. This could speed up the reuse of drugs to treat or prevent type 1 diabetes, the researchers say.

This work represents the largest and most diverse study in type 1 diabetes that identifies the most likely causal genetic variants associated with risk, their target genes, and genes involved in other autoimmune diseases with targets known medicinal products. Using these results, we hope that the number of plausible genetic variants will be reduced, that their function and genetic targets will be clarified, and that existing drugs used in other diseases can be tested for their impact on delaying cancer. onset of type 1 diabetes or improved treatment results. “

Stephen S. Rich, PhD, Research Fellow, University of Virginia School of Medicine and Public Health Genomics Center

About type 1 diabetes

Formerly known as juvenile diabetes, type 1 diabetes can affect both children and adults. In type 1 diabetes, the body’s own immune system attacks the insulin-producing beta cells in the pancreas, causing the body to not make enough insulin, a hormone that helps the body burn sugar for fuel. . Treatment is to replace insulin, but it is not a cure.

Type 1 diabetes increases the risk of heart problems, strokes, nerve damage and vision loss, and can even lead to pregnancy complications and miscarriages. It also reduces blood flow to the feet, which means that small, untreated injuries can turn into serious problems, eventually requiring amputation.

The new type 1 diabetes study looked at 61,427 participants, twice the size of the previous largest study. Most of the previous research has focused on the risk of type 1 diabetes in people of European descent, while the new findings provide important information about the “genetic landscape” of type 1 diabetes in people of European descent. African, Asian and others, report the researchers in a new scientific article.

“Increasing diversity in all aspects of research is ethically important, but, in addition, diverse populations potentially provide unique genetic information that can reduce the number of suspected causal variants of risk, as well as interactions with new, non-genetic risk factors, ”said Rich, of the AVU’s Department of Public Health Sciences. “For example, in populations of African descent, there is evidence in some genomic regions that risk variants of type 1 diabetes have reduced the list of causal variants, while in other regions, risk variants are distinct from those of populations of European descent. the data is essential for implementing genetic risk scores to identify children at high genetic risk for future screening and entry into immune intervention trials. “

New findings on diabetes

In total, scientists have identified 78 regions on our chromosomes where there are genes that influence our risk for type 1 diabetes. Of these, 36 regions were previously unknown.

In addition, researchers have identified specific and natural genetic variations that influence risk and determined how these variations act on particular types of cells. They were then able to use their findings to identify and prioritize potential drug targets.

Of the potential targets, a dozen are being investigated in ongoing or completed clinical trials for autoimmune diseases. For example, the IL23A gene has been successfully targeted in the treatment of inflammatory bowel disease and psoriasis. Targeting this gene could also prove useful in the fight against type 1 diabetes, the researchers say.

Although more studies are needed, the work of scientists has broadened our understanding of type 1 diabetes in different groups and produced many promising leads that may ultimately benefit patients.

“Based on this work, we are now approaching knowledge of almost 90% of the genetic risk for type 1 diabetes, which is about half of the total risk for the disease,” said Rich. “This work brings us closer to the goal of precision medicine in type 1 diabetes, where we can use genetics to help identify those at risk for autoantibody screening and early detection, with information genetics on therapies that would improve the search for a cure. “

Published results

The researchers published their findings in the scientific journal Genetics of nature. The research team consisted of Catherine C. Robertson, Jamie RJ Inshaw, Suna Onengut-Gumuscu, Wei-Min Chen, David Flores Santa Cruz, Hanzhi Yang, Antony J. Cutler, Daniel JM Crouch, Emily Farber, S. Louis Bridges Jr., Jeffrey C. Edberg, Robert P. Kimberly, Jane H. Buckner, Panos Deloukas, Jasmin Divers, Dana Dabelea, Jean M. Lawrence, Santica Marcovina, Amy S. Shah, Carla J. Greenbaum, Mark A. Atkinson , Peter K Gregersen, Jorge R. Oksenberg, Flemming Pociot, Marian J. Rewers, Andrea K. Steck, David B. Dunger, Type 1 Diabetes Genetics Consortium, Linda S. Wicker, Patrick Concannon, John A. Todd and Rich.

The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (including grants U01 DK062418, DP3 DK111906, R01 DK1115694), JDRF (4-SRA-2017-473-AA) and the Centers for Disease Control, among many others. A complete list is included in the document.

Source:

University of Virginia Health System

Journal reference:

Robertson, CC, et al. (2021) Fine-mapping, trans-ancestral, and genomic analyzes identify causal variants, cells, genes, and drug targets in type 1 diabetes. Genetics of nature. doi.org/10.1038/s41588-021-00880-5.


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