Largest Type 1 Diabetes Genetic Study Identifies New Causal Variants, Drug Targets

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An international group of researchers has completed what they say is the “largest and most diverse” genetic study of type 1 diabetes to date that has enabled them to identify new causal variants and potential drug targets for new therapies.

The study found 12 genes linked to type 1 diabetes that have also been linked to other autoimmune diseases such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis, and used to develop drugs for These conditions. The team believe this information could be used to find new treatments for this type of diabetes.

“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 known drug targets, ”said researcher Stephen Rich, of the University of Virginia School of Medicine and its Center for Genomics in Public Health, in a press release.

“With the help of 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 the disease. delayed onset of type 1 diabetes or improved treatment results. . “

As reported in the journal Genetics of nature, the study involved 61,427 (7,117 of non-European ancestry – mixed Africans, East Asians and others mixed) participants recruited by the University of Virginia and the Feinstein Institute in the United States and the Sanger Institute and Cambridge University in the UK

The team discovered 36 new regions of the genome linked to an increased risk of type 1 diabetes. They found that these variants tended to cluster in chromatin accessed by immune cells such as CD4 + effector T cells.

Researchers highlight a causal variant in the BACH2 gene they discovered. This gene encodes a transcriptional regulatory protein and variants of this gene have been linked to autoimmune diseases such as vitiligo in the past. The variant they discovered in this study was found to decrease the accessibility of enhancer and expression of BACH2 in T cells.

The researchers used what is called a priority index algorithm to search for new drug targets for type 1 diabetes. This combines genetic associations with genome annotations, regulatory maps, and protein-protein networks.

Of the 50 main target genes identified by the researchers, 13 had not previously been identified as potential targets, including genes such as STAT4, RGS1, and CXCR6 and 12 had previously been identified as targets for other autoimmune diseases.

“An example is IL23A, which has been successfully targeted in the treatment of inflammatory bowel disease and psoriasis, ”the researchers write. “IL-23 inhibitors are being investigated for use in T1D (ClinicalTrials.gov identifiers NCT02204397 and NCT03941132). Our results provide genetic support for these assays.

Researchers now plan to continue their discoveries and use them to help improve treatment and diagnostic options for people with and at risk for type 1 diabetes.

“Based on this work, we are now approaching the knowledge of almost 90% of the genetic risk of type 1 diabetes, which is about half of the total risk of the disease,” commented 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. “


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