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'Core' Genes for Type 1 Diabetes Uncovered

Researchers said their discovery of nine 'core' genes central to the development of type 1 diabetes could unlock new immune system pathways for targeting by immunotherapies.

A team from the University of Edinburgh set out to identify which genes were at the root of type 1 diabetes risk, and which had only small effects. The investigation was backed by Diabetes UK, whose director of research, Dr Elizabeth Robertson, said: "Type 1 diabetes is a constant balancing act of blood sugar checks and insulin injections. We desperately need to find ways to prevent, delay and treat the condition, to spare hundreds of thousands of people the burden of managing their diabetes, day in, day out."

The charity stressed that despite an autoimmune reaction in the body being acknowledged as the reason for type 1 diabetes developing, "no one knows exactly what causes it".

About 8% of people with diabetes have type 1, which equates to nearly 400,000 people in the UK. 

Long Range Effects of Risk Variants Studied

The study, published in the American Journal of Human Genetics, described how the "omnigenic" hypothesis postulated that most of the genetic effects on a typical complex trait are mediated through "weak trans-effects of common variants that coalesce on expression" of a relatively sparse set of "core" effector genes in relevant tissues.

To test the hypothesis, and analyse how different genes impacted the risk of developing type 1 diabetes, the researchers developed a new method to sum the effects of genetic variants across the entire genome.

The team examined genetic data from 4964 cases of type 1 diabetes and 7497 controls by using summary statistics to calculate aggregated - excluding the HLA region - trans-scores for gene expression in blood. 

Professor Paul McKeigue, co-lead investigator, said: "Until now researchers have studied the short-range effects of risk variants on nearby genes and found no obvious link to the risk of conditions or ways to treat them. Our study focused instead on the long-range effects of these risk variants on genes elsewhere on the genome."

Understanding of Genetic Architecture of Type 1 Diabetes Reshaped

The researchers identified nine 'core' genes through which common genetic variants - all linked to the immune system - acted to cause type 1 diabetes. Three of these -STAT1, CTLA4, FOXP3 – were genes in which variants caused monogenic forms of autoimmune diabetes, explained the authors. 

"Seven of these genes play a crucial role in regulating the immune cells that attack the pancreas in type 1 diabetes," emphasised the authors. Two of the genes were linked to part of the immune system's first line of defence, a part of the immune system that had not previously been associated with type 1 diabetes.

"These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D," said the authors.

Brink of a New Era in Type 1 Diabetes Management

The research had "broken new ground" in the understanding of genes that underpinned type 1 diabetes, and how they contributed to the immune attack that causes the condition, Dr Robertson pointed out.

The researchers hoped their findings would lead to new treatments that could prevent the immune system attack that causes type 1 diabetes, further delay the onset of type 1 diabetes in those at high risk, or preserve pancreatic beta cells that survive the immune attack following a diagnosis of type 1 diabetes.

Professor McKeigue enthused that some of the newly identified 'core' genes for type 1 diabetes were "potential therapeutic targets".

"The discovery that these 'core' immune system genes are central to the development of type 1 diabetes opens the door to a raft of new targets for immunotherapies that could prevent, delay or treat type 1 diabetes early on," Dr Robertson postulated.

She expressed her belief, and delight, that type 1 diabetes therapies were on the "brink of a new era" that could see the management of the condition being "transformed from a lifelong condition to one that can be prevented, treated and ultimately cured".