Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility
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In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility.
We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9–21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes.
Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (>7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion.
At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.
KeywordsChildren Diabetes-associated autoantibodies GAD antibodies HLA IA-2 antibodies Insulin autoantibodies Islet cell antibodies Prediction Prevention Type 1 diabetes
Type 1 Diabetes Prediction and Prevention
Islet antigen 2
Islet cell antibodies
The authors acknowledge all participants in the DIPP study and physicians, nurses and technicians at the DIPP study centres and laboratories. Some of these data were presented as an abstract at the 51st EASD Annual Meeting, Stockholm, Sweden, 14–18 September 2015.
The study data are available on reasonable request from the corresponding author. The data are not publicly available due to the protection of the identity of the study participants and their clinical data.
This work was supported by the following grants: JDRF International (grant nos 4-1998-274, 4-1999-731, 4-2001-435); European Union (grant no. BMH4-CT98-3314); Novo Nordisk Foundation; Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012–2017, Decision no. 250114 and grant 292538); Special Research Funds for University Hospitals in Finland; Diabetes Research Foundation, Finland; Sigrid Juselius Foundation; and Finska Läkaresällskapet.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
PMP collected and researched the data and substantially contributed to the study conception and design, data acquisition, analysis and interpretation, and drafted the first version of the article. HS substantially contributed to data acquisition, contributed to discussions and edited the manuscript. MK, JL, A-PL, JI, JT, RV and PV generated data, contributed to discussions and revised the article critically for important intellectual content. All authors gave their final approval of the version to be published. MK designed the study, is the guarantor of this work, had full access to all data in the study, and takes responsibility for the data integrity and accuracy of the data analysis.
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