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Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.
Diabetologia. 2017 07; 60(7):1284-1293.D

Abstract

AIMS/HYPOTHESIS

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS/INTERPRETATION

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.

Authors+Show Affiliations

Children's Hospital, University of Helsinki and Helsinki University Hospital, P.O. Box 22, FI-00014, Helsinki, Finland. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.Children's Hospital, University of Helsinki and Helsinki University Hospital, P.O. Box 22, FI-00014, Helsinki, Finland. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.Children's Hospital, University of Helsinki and Helsinki University Hospital, P.O. Box 22, FI-00014, Helsinki, Finland. mikael.knip@helsinki.fi. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland. mikael.knip@helsinki.fi. Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland. mikael.knip@helsinki.fi. Folkhälsan Research Center, Helsinki, Finland. mikael.knip@helsinki.fi.

Pub Type(s)

Journal Article
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28364254

Citation

Pöllänen, Petra M., et al. "Characterisation of Rapid Progressors to Type 1 Diabetes Among Children With HLA-conferred Disease Susceptibility." Diabetologia, vol. 60, no. 7, 2017, pp. 1284-1293.
Pöllänen PM, Lempainen J, Laine AP, et al. Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility. Diabetologia. 2017;60(7):1284-1293.
Pöllänen, P. M., Lempainen, J., Laine, A. P., Toppari, J., Veijola, R., Vähäsalo, P., Ilonen, J., Siljander, H., & Knip, M. (2017). Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility. Diabetologia, 60(7), 1284-1293. https://doi.org/10.1007/s00125-017-4258-7
Pöllänen PM, et al. Characterisation of Rapid Progressors to Type 1 Diabetes Among Children With HLA-conferred Disease Susceptibility. Diabetologia. 2017;60(7):1284-1293. PubMed PMID: 28364254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility. AU - Pöllänen,Petra M, AU - Lempainen,Johanna, AU - Laine,Antti-Pekka, AU - Toppari,Jorma, AU - Veijola,Riitta, AU - Vähäsalo,Paula, AU - Ilonen,Jorma, AU - Siljander,Heli, AU - Knip,Mikael, Y1 - 2017/03/31/ PY - 2016/05/30/received PY - 2017/02/17/accepted PY - 2017/4/2/pubmed PY - 2018/5/10/medline PY - 2017/4/2/entrez KW - Children KW - Diabetes-associated autoantibodies KW - GAD antibodies KW - HLA KW - IA-2 antibodies KW - Insulin autoantibodies KW - Islet cell antibodies KW - Prediction KW - Prevention KW - Type 1 diabetes SP - 1284 EP - 1293 JF - Diabetologia JO - Diabetologia VL - 60 IS - 7 N2 - AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/28364254/Characterisation_of_rapid_progressors_to_type_1_diabetes_among_children_with_HLA_conferred_disease_susceptibility_ L2 - https://doi.org/10.1007/s00125-017-4258-7 DB - PRIME DP - Unbound Medicine ER -