Diagnosing Type 1 Diabetes before Symptoms Strike
Genetic screening can mean that people at risk of type 1 diabetes get earlier treatment and better outcomes
This article is part of “Innovations In: Type 1 Diabetes,” an editorially independent special report that was produced with financial support from Vertex.
There is currently no cure for type 1 diabetes, a chronic condition in which the body’s immune system attacks and kills insulin-producing beta cells in the pancreas. Knowing someone’s genetic predisposition to type 1 diabetes, however, can help doctors identify whom to flag for follow-up tests. It can also lead to earlier adoption of therapeutics to manage the disease or delay its onset. “There’s tremendous power in terms of understanding the genetics of type 1 diabetes,” says Todd Brusko, director of the Diabetes Institute at the University of Florida. As more therapies become available, he adds, the eventual hope is to use genetic profiling to determine who will respond best to one drug versus another.
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In the U.S., around one in 300 people develops type 1 diabetes. Although the disease is best known for manifesting in children, adults account for almost half of new diagnoses. Scientists still don’t know what triggers it. Environmental factors seem to play a crucial role in promoting the disease’s development and progression, but the exact causative agents are unknown. “We know less about the environmental factors than we know about the genetic factors,” Redondo says.
In a large study called TEDDY (for “the environmental determinants of diabetes in the young”), launched in 2004 in Europe and the U.S., researchers followed 8,676 individuals with high genetic risk to try to identify triggers for type 1 diabetes. They found just one consistent environmental factor linked to higher likelihood of acquiring the disease: early infection with enteroviruses, a type of virus that can infect beta cells. Not all children who get these common infections go on to develop type 1 diabetes, though, so additional factors are probably at play. In addition, the incidence of the disease has been increasing steadily over the past 60 years, suggesting that some change in environmental exposures or the removal of protective factors—or both—may be involved.
Genetics accounts for about half of a person’s risk of developing the disease, meaning what is written into someone’s DNA is “not destiny,” Rich says. “If you have a high [genetic] risk, it doesn’t mean you’ll get it, and if you have a not-high risk, that doesn’t mean you’re protected.”
For people with a close relative with type 1 diabetes, the risk goes up to about 18 in 300. Those with an identical twin with the disease have the highest risk—about one in two. They are 150 times likelier to develop the illness than someone with no family history and eight times likelier than someone with a parent or sibling who has been diagnosed. Even so, around 90 percent of people who are diagnosed with type 1 diabetes have no relatives with the disease. Until recently, population-level genetic screening, which would include individuals regardless of their known risk factors for the condition, was not a practical option. But new breakthroughs have begun to change that.
Scientists have identified at least 90 regions in the human genome that hold genes connected to type 1 diabetes. Researchers are most interested in a gene cluster called the human leukocyte antigen system (HLA), which encodes proteins that help the immune system distinguish self from nonself. This gene group accounts for around half of a person’s genetic risk of developing the disease. Because it helps to protect us from infections, HLA is also highly variable, says Mark Anderson, director of the Diabetes Center at the University of California, San Francisco. “There’s selective pressure for us to have different HLA genes because that way, a virus or bacterium that comes along won’t wipe everyone out.”
In 2015 Oram and his colleagues developed the first version of what is now one of the most widely used tests for type 1 diabetes genetic risk, administered primarily in research settings (the U.S. has yet to approve any test for type 1 diabetes risk for real-world use in doctor offices). Rather than just adding up the contribution of each variant, Oram and his colleagues’ test incorporates the complex interactivity of various alleles with one another, including ones with protective effects. They also incorporated dozens of other non-HLA sites—mostly from genes also related to the immune system—that contribute small amounts of individual risk but can add up to larger cumulative risk.
The original version of the test examined just 10 alleles and “worked pretty well,” Oram says. The latest version, developed in 2019, uses 67 alleles and produces “highly sophisticated” results, Redondo says, adding that it now represents “the golden standard to date.”
When Oram originally developed his test, he did not have risk prediction in mind; rather he was trying to decipher the type of diabetes in a group of his patients. The individuals he was working with, who were 20 to 40 years old, had overlapping features of type 1 and type 2 diabetes. People who fall into this “gray area” of symptoms are commonly misdiagnosed, he says. While brainstorming solutions over coffee with a colleague, Oram realized a genetic test could offer clues for people with a less clear presentation of the disease.
After successfully developing the test, Oram learned that other research groups were interested in tests to determine genetic risk for type 1 diabetes. Fortunately his test “also turned out to be really good for that,” he says.
With Oram’s test, doctors can identify the highest-risk individuals, who can then get tested for the antibodies that attack the body’s beta cells. “If you do HLA screening followed by antibody testing at specific ages, you’ll pick up far and away the vast majority of cases,” says William Hagopian, a research professor of pediatrics at the Indiana University School of Medicine. Investigators leading vaccine and pharmaceutical trials for type 1 diabetes are also using genetic tests to maximize efficiency and funding by identifying participants who are most likely at risk for the disease.
People aware of their risk might also be on the lookout for symptoms such as excessive urination and lethargy; when those pop up, people can seek treatment before they develop diabetic ketoacidosis (DKA), a potentially life-threatening condition caused by a lack of insulin. Among those who don’t know they are at risk, about 40 percent wind up in this critical state, but that number drops as low as 4 percent for those who are aware. “If people can identify some of the symptoms of progression toward disease, they could go to a GP instead of an ER and prevent a real crisis,” Brusko says.
Type 1 diabetes has been most prevalent among people of European ancestry. It does occur in those of African, Hispanic and Asian ancestry, but the vast majority of data used to inform genetic screening results is from people of white, European descent, Rich says. This lack of representation is problematic for people of different ancestries because genetic risk factors differ across populations.
In an unpublished study, Rich and his colleagues tested how well the most common HLA variants used in genetic tests predicted risk in people with European, Hispanic, African American or Finnish ancestry. They found that genetic ancestry for important HLA regions—and the many other regions of the genome associated with type 1 diabetes risk—does not transfer well from one population to another. “One of the biggest needs in the field is to understand what confers genetic risk in a much more diverse genetic ancestry,” Brusko says.
Scientists are working to fill this gap. For instance, Breakthrough T1D, a nonprofit organization funding research on type 1 diabetes, provides grants of up to $900,000 for research aimed at improving the prediction power of genetic risk scores across diverse populations. For the next version of the genetic risk score test, the plan is to incorporate specific HLA types present in Africans, East Asians, and several other groups, says Hagopian, who collaborates with Oram.
What to do with the information that testing would generate, though, is a more complicated question. Health-care officials would have to set up a system for contacting the families of babies at high risk to appropriately communicate the results. There would also need to be a system to remind families to get their child checked for autoantibodies at certain intervals. States handle newborn screenings differently, so each would have to come up with its own solutions. This issue is “a major complication that has to be figured out,” says Rich, who continues to field e-mails and calls from parents interested in the testing.
As the science is refined, more treatment options will be made available, and the uncertainty surrounding who will and will not go on to develop type 1 diabetes is likely to be narrowed. Redondo and her colleagues are pursuing a large project using genetic risk scores and other variables to try to more accurately predict disease development. They are also working on models to determine who will respond best to new disease-modifying therapies. As Redondo says, “personalizing prevention of type 1 diabetes is the goal.”
Rachel Nuwer is a science journalist and author. Her latest book is I Feel Love: MDMA and the Quest for Connection in a Fractured World (Bloomsbury, 2023). Follow her on Bluesky @rachelnuwer.bsky.social
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