LISBON -- Genetic links to type 1 diabetes vary by age of onset, supporting the emerging idea of heterogeneity in the disease, researchers reported.
The combination of alleles known as DR3/DR4 traditionally seen as the strongest risk for type 1 diabetes in studies from young-onset cases only held that top slot among people 25 and younger in analysis of the entire U.K. Biobank with more than 25 years of data.
After age 26, homozygous DR4/DR4 actually carried at least as great a risk as did DR3/DR4, accounting for 42% and 37% of excess cases in the population, respectively, compared with 24% and 54% in childhood-onset cases (P<0.23 and P<0.001).
The risk from DR3/DR3 remained stable from childhood through adulthood, at 21% of excess cases in the population, Nicholas Thomas, BM, of the University of Exeter, England, and colleagues reported here at the European Association for the Study of Diabetes meeting.
The mean age at diagnosis in the Biobank was 21 with DR3/DR4, 26 with DR3/DR3, and 31 with DR4/DR4.
The strongest known protective allele, DR15, remained so through age 50 in the study.
All those allele combinations together are still rare, totaling less than 6% prevalence in the population, Thomas noted.
However, there are some important implications from finding heterogeneity, he told MedPage Today at a press conference where the findings were presented. "Where it might be helpful is we're developing type 1 genetic risk scores to help as part of aiding some of the diagnostic uncertainty about late-onset diabetes.
"It may be, because we used the odds ratios of developing diabetes traditionally associated with young-onset type 1 diabetes to help determine our risk store, that for individuals diagnosed later we need to change those odds ratios slightly and change that risk score.
"I think the most important thing, though, is it shows us it is different, that there is heterogeneity in type 1 diabetes, heterogeneity in the immune process that goes with type 1 diabetes whether it's diagnosed in childhood or young adulthood or later onset. That's important when it comes to studying type 1 diabetes, but also when it we come to think about immunotherapies and treating type 1 diabetes that we might be treating a subtly different disease at different ages."
Daniel Witte, PhD, of Denmark's Aarhus University, agreed. "The interesting thing, like you said, is the heterogeneity. Increasingly we're realizing that the old type 1, type 2 distinction is not as clear cut as we were told ... It leads up to having to know more about the exact type of disease that you're treating before treating perhaps in the future."
49 - New insights into HLA in type 1 diabetes from population analysis: DR4 homozygosity specifically predisposes to type 1 diabetes after 30 years
AuthorsN.J.M. Thomas, S.E. Jones, M. Weedon, R. Oram, A. Hattersley;
Exeter University, Exeter, UK.Disclosures N.J.M. Thomas:
Background and aims: The major genetic determinants of Type 1 diabetes (TID) are the DR3, DR4 polymorphisms of class II HLA genes encoding DQ and DR. DR3/DR4 carriers show increased risk of T1D relative to DR3/DR3 and DR4/DR4 carriers in children and young adults but it is not known if this relative risk persists in individuals diagnosed with T1D later in life.
Materials and methods: We analysed the development of diabetes (aged 0-60 years) in subjects with highest risk HLA groups DR3/DR3, DR3/DR4 and DR4/DR4 (allele frequencies 2.4%, 2.9% 1.1%) in 120,192 UK individuals from the UK Biobank. We used the Exeter susceptibility-exclusion method with HLA group X/X being assumed to have no T1D.

Results: The highest risk genotypes represent 6.4% (7,676/120,192) of the population but contribute 61% (228/376) of all cases of T1D. In high risk HLA groups DR3/DR3, DR3/DR4 and DR4/DR4 there were marked differences in likelihood of developing T1D (1.2%, 4.2%, 3.5%, p<0.001) and in the mean age of diagnosis (17, 28, 38 years p<0.001). The majority 71% (32/45) of T1D cases associated with DR4/DR4 are diagnosed over 30 years of age unlike 26%(9/34) DR3/DR3 and 40%(59/149) DR3/DR4 p<0.001. (Fig.)
Conclusion: Whilst all three major genotypes greatly increase risk of T1D throughout life, population analysis has shown for the first time that DR4/DR4 specifically predisposes to T1D over 30 years of age and carriers of this genotype have the highest risk for development of late-onset T1D. This result is consistent with heterogeneity in age of diagnosis reflecting heterogeneity in immune mechanisms in T1D.
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