Immunological, genetic factors associated with rapid progression to type 1 diabetes
medwireNews: Study results suggest that autoantibody-positive children who progress rapidly to type 1 diabetes have higher antibody titers and distinct genetic characteristics compared with those who develop the disease more slowly or do not progress to diabetes.
“Such children might benefit from early metabolic surveillance and early treatment to protect them from developing diabetic ketoacidosis,” say researcher Mikael Knip (University of Helsinki, Finland) and colleagues.
Of 7410 children with HLA-defined predisposition to type 1 diabetes who participated in the DIPP longitudinal birth cohort study, 20.9% tested positive for at least one diabetes-associated autoantibody and 16.0% developed type 1 diabetes over a median follow-up of 16.2 years.
In all, 16.9% of 248 children who developed diabetes were classified as rapid progressors – defined as progression to clinical diabetes within 1.5 years of autoantibody seroconversion – with a median time from seroconversion to diagnosis of 0.51 years.
By comparison, the median time to diagnosis was 5.37 years among 206 slow progressors. The remaining 1302 autoantibody-positive children did not develop diabetes.
Rapid progressors had significantly higher titers of islet cell antibodies and islet antigen 2 autoantibodies at the time of seroconversion than those who developed diabetes more slowly (34.5 vs 10.0 relative units and 52.5 vs 16.4 relative units, respectively). And among carriers of the high-risk HLA genotype, rapid progressors were more likely to be homozygous for the major G allele of the FUT2 gene than slow progressors (68 vs 28%).
Moreover, compared with autoantibody-positive children who did not develop diabetes during follow-up, rapid progressors were significantly younger at seroconversion (6.0 vs 1.5 years), were significantly more likely to carry both the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, and be positive for islet cell antibodies and autoantibodies to insulin, glutamic acid decarboxylase, and islet antigen 2.
Therefore, “individuals with aggressive islet autoimmunity and rapid progression to type 1 diabetes can be identified from the general population by demographic, genetic and immunological characteristics present at seroconversion,” say the researchers.
In analyses by age, Knip and colleagues observed that rapid progression occurred predominantly before 5 years of age, as seen in 36 children, but also after early puberty (8–14 years) in six children..
“The double-peak age profile in rapid progressors documents for the first time that rapid progression to clinical disease may occur in children at early puberty and not exclusively in children aged under 5 years,” concludes the team in Diabetologia.
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