Two Different Roads Into Type 1
Two Different Roads Into Type 1
A genome study split type 1 diabetes by a genetic marker almost nobody has had tested. The two halves turned out to look less alike than expected.
Researchers at the University of Exeter and UC San Diego did something with type 1 genetics that had not been done before. Writing in Diabetologia on August 31, 2026, they took 9,091 people with type 1 and 14,157 people without it, sorted everyone by which high-risk HLA haplotype they carried, and ran the genetics separately in each group. The paper is open access.
Two haplotypes do most of the heavy lifting in type 1 risk. They are called DR3 and DR4, and by the researchers' own accounting roughly 90% of people of European ancestry who develop type 1 carry one or both. Which one a person carries tracks loosely with which islet antibody shows up first, and with how old they are at diagnosis.
Compared side by side, the two groups shared less genetic ground than the researchers expected. That result did not appear out of nowhere. It has been assembling for about a decade, in three other places first.
How big a gap is 0.68?
A genetic correlation of 1.0 would mean the measured genetic effects in the two groups line up almost perfectly. The team ran two comparisons as a yardstick. Splitting the same people by sex gave 0.88. Splitting them by whether they were diagnosed before or after age 8 gave 0.96 — close to no genetic difference at all.
Against those, 0.68 is a real separation, and the paper notes it sits near the correlation between Crohn's disease and ulcerative colitis. Worth being precise: the gap against the age split cleared statistical significance, and the gap against the sex split fell just short of it. Worth naming plainly: this work had industry funding alongside its university, government and nonprofit support. It received research funding from Randox Laboratories, and the lead author’s PhD studentship is funded by Randox — a diagnostics company that two of the authors hold a separate grant with, to develop a type 1 genetic risk score biochip. Several authors also disclose consulting or honoraria relationships with pharmaceutical companies.
One locus separated cleanly. Variants near IL2, a gene central to T cell activation, had a larger effect in DR4 carriers than in DR3 carriers, and it was the only locus to survive correction for multiple testing. Three others showed weaker signals that did not. Where the pattern gets broader is in which cellular machinery each group's variants landed in — and putting three groups side by side, a gradient appears.
The question underneath
There is a tension inside this paper worth sitting with. The framework most of this work rests on defines its two groups by age at diagnosis. But when this study split people that way, the genetic correlation came back at 0.96 — the two age groups looked nearly identical. Splitting by HLA produced the wider gap.
Which raises a question the field has not settled: which measurement is doing the real work?
This is the framework built from pancreas tissue. Children diagnosed before 7 show one pathology; those diagnosed after 12 show another. That evidence is direct rather than inferred — someone looked at the tissue. Age is also free, universal, and already sitting in every chart, which makes it usable in a way a genetic test is not.
An editorial read of the new findings would flip the order. Age at diagnosis may describe how fast the process ran rather than which process ran. HLA type is fixed at conception, never drifts, cannot go transiently undetectable the way an antibody can, and in this study separated the genetics more sharply than age did. The paper's own recommendation is that future trials consider DR3 and DR4 status in their design.
The researchers are direct about the limits, and their list is the most useful part of the paper. HLA type is only a partial stand-in for which antibody appears first. Everyone carrying both DR3 and DR4 was left out entirely, because they cannot be assigned to one group — and that combination carries the highest risk of all. The study ran only in people of European ancestry, so how well the findings generalize to other ancestry groups is not yet known. And the mast cell result rests on a single comparison that barely cleared its threshold.
Almost nobody living with type 1 knows their HLA type. It does not appear on a discharge summary, it never changes, and it may turn out to matter.
An editorial observationWhat this changes right now
Nothing, for anyone's day-to-day management. HLA typing is not part of routine type 1 care, no treatment decision currently depends on it, and nothing in this paper is approved as a way to choose a therapy. Insulin, pump settings, and CGM alarms are untouched by any of this. It is a study about where the disease comes from, not about how to manage it.
Where it could land is in trial design. If prevention studies start recording HLA background and reporting results by group, the field would learn faster why a drug helps one family and not another — which is the authors' own recommendation.
There is also a smaller group with a more immediate stake: the roughly 10% who carry neither haplotype, are diagnosed later, have fewer detectable antibodies, and sometimes get labeled type 2 for years before anyone revisits it. Anyone who has wondered whether their own diagnosis got sorted into the wrong bin has a reasonable question to raise — not a demand for a genetic test, but a conversation about what was measured and when. That is a conversation to have with a doctor who knows the whole history, not a decision to make from a study.
The main study. Luckett AM, McGrail C, Murrall K, et al. Genetic association stratified by HLA-DR3 and HLA-DR4 status reveals heterogeneity in pathways of progression to type 1 diabetes. Diabetologia, 31 August 2026. Open access. Funded by university, government and nonprofit sources, plus research funding from Randox Laboratories; the lead author holds a Randox PhD studentship, and two authors hold a Randox grant to develop a type 1 genetic risk score biochip. Authors separately disclose consulting and honoraria relationships with several pharmaceutical companies.
People with neither haplotype. McGrail C, Chiou J, Elgamal R, et al. Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes. Diabetes Care 2025;48(2):202–211.
Antibody order in children. Krischer JP, Lynch KF, Schatz DA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 2015;58(5):980–987.
Pancreas tissue and age at diagnosis. Leete P, Oram RA, McDonald TJ, et al. Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis. Diabetologia, 2020.
Mast cells in donated pancreas tissue. Martino L, Masini M, Bugliani M, et al. Mast cells infiltrate pancreatic islets in human type 1 diabetes. Diabetologia 2015;58(11):2554–2562.
IL2 and age at diagnosis. Howson JMM, Cooper JD, Smyth DJ, et al. Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes. Diabetes 2012;61(11):3012–3017.
Teplizumab subgroups. Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine 2019;381(7):603–613. Subgroup findings were prespecified but not adjusted for multiple comparisons.
How to read this evidence. Every study above is a genetic association or tissue study, not a test of a treatment. They describe patterns across large groups of people; none of them predicts what will happen to any one person. Association is not cause: finding that a variant is more common in a group does not show that it drives the disease. The teplizumab subgroup numbers come from prespecified analyses that were not adjusted for multiple comparisons and have been described in the literature as exploratory. HLA typing is not part of standard type 1 care, and no therapy is approved to be selected on the basis of DR3 or DR4 status.
This post is for educational purposes only and is not medical advice. Nothing here is a recommendation to start, stop, or change any medication. Talk with your doctor before making any changes to your care.
Two Different Roads Into Type 1
A genome study split type 1 by HLA background and found the two groups less genetically alike than expected. It is a study about where the disease comes from, not about how it is managed, and nothing in it changes anyone’s care.
What the research shows
- Luckett et al., Diabetologia, August 2026: 9,091 people with type 1 and 14,157 without, sorted by whether they carried the DR3 or the DR4 haplotype. Setting the HLA region aside, the two groups’ genetic effects correlated at 0.68.
- Splitting the same people by age at diagnosis gave 0.96, and by sex 0.88. The gap against the age split cleared statistical significance; the sex gap fell just short.
- DR4 risk variants clustered in T cell machinery. DR3 variants clustered in mast cell regulatory regions and pathways for secretion and cellular stress.
- IL2 was the only locus whose difference between groups survived correction for multiple testing.
- A companion study (McGrail et al., Diabetes Care, 2025) found the roughly 10% who carry neither haplotype lean toward antigen presentation, innate immunity and beta cell pathways instead.
What it does not show
- Not a new diagnosis, subtype or test. No category changed and no one’s care changes because of it.
- Everyone carrying both DR3 and DR4 was excluded, because they cannot be assigned to one group — and that combination carries the highest risk of all.
- The study ran only in people of European ancestry, so how well the findings generalize to other ancestry groups is not yet known.
- The mast cell result rests on a single comparison at p=0.043. A lead, not a finding.
- These are association studies. Finding a variant more often in a group does not show that it drives the disease.
If you live with type 1
- HLA typing is not part of routine type 1 care, and no treatment decision currently depends on it.
- The likely near-term consequence is trial design — recording HLA background and reporting results by group, which is the authors’ own recommendation.
- If your own diagnosis was ever unclear — later onset, few detectable antibodies, an initial type 2 label — that is a reasonable thing to raise with the doctor who knows your whole history.
Funding. The main study had industry funding alongside university, government and nonprofit support, including research funding and a PhD studentship from Randox Laboratories.
Educational purposes only and not medical advice. Talk with your doctor before making any changes to your care. — juiceboxpodcast.com
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