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

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Woman injecting insulin, daily diabetes care during COVID-19
[Source: martin-dm/Getty Images]

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

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

“This work represents the largest, most ancestry-diverse study of type 1 diabetes that identifies the most likely causal genetic variants associated with risk, their target genes and those genes that are implicated in other autoimmune diseases with known drug targets,” said researcher Stephen Rich, of the University of Virginia School of Medicine and its Center for Public Health Genomics, in a press statement.

“Using these results, we hope that the number of plausible genetic variants will be reduced, their function and gene targets clarified, and existing drugs used in other diseases can be tested for their impact on delaying onset of type 1 diabetes, or improved treatment outcomes.”

As reported in the journal Nature Genetics, the study included 61,427 (7,117 of non-European ancestry­—African admixed, East Asian and Other admixed) participants recruited by the University of Virginia and Feinstein Institute in the U.S. and the Sanger Institute and University of Cambridge in the U.K.

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

The researchers highlight a causal variant in the BACH2 gene that they discovered. This gene encodes a transcription regulator protein and variants in this gene have been linked to autoimmune conditions such as vitiligo in the past. The variant they discovered in this study was shown to decrease enhancer accessibility and the expression of BACH2 in T cells.

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

Of the top 50 gene targets 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 conditions.

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

The researchers now plan to follow up their findings further and use them to help improve treatment and diagnostic options for people with and at risk of type 1 diabetes.

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

“This work moves us closer to the goal of precision medicine in type 1 diabetes, when we can use genetics to help identify those at risk for autoantibody screening and early detection, with genetic insights to therapies that would enhance the search for a cure.”

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