title: Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.
abstract: 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.
authors.affiliation: 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.
authors.forename: Petra M
authors.initials: PM
authors.lastname: Pöllänen
authors.affiliation: Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lempainen
authors.affiliation: Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Laine
authors.affiliation: Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Vähäsalo
authors.affiliation: Immunogenetics Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: 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.
authors.forename: Heli
authors.initials: H
authors.lastname: Siljander
authors.affiliation: 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.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006680:HLA Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D050417:Insulin-Secreting Cells / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D013997:Time Factors; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D005968:Glutamate Decarboxylase
keywords: Children; Diabetes-associated autoantibodies; GAD antibodies; HLA; IA-2 antibodies; Insulin autoantibodies; Islet cell antibodies; Prediction; Prevention; Type 1 diabetes