title: Genetic risk determines the emergence of diabetes-associated autoantibodies in young children.
abstract: Timing of onset of autoimmunity is a prerequisite for unmasking triggers and pathogenesis of type 1 diabetes. We followed 4,590 consecutive newborns with 8 or 3% HLA-DQB1 conferred risk for type 1 diabetes at 3-, 6-, or 12-month intervals up to 5.5 years of age. Islet cell autoantibodies (ICAs) and, in the 137 children with ICAs, insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and IA-2 protein autoantibodies (IA-2As) were measured. Children with high genetic risk developed ICAs more often than those with moderate risk (log-rank P = 0.0015); 85 and 91% remained ICA negative by 5 years of age, respectively. The time of appearance of biochemical autoantibodies was then compared with the appearance of ICAs. IAAs and GADAs emerged usually before ICAs (means -1.8 and -1.5 months, respectively) and IA-2As after ICAs (mean 2.0 months). Ninety-five percent of all IAAs, GADAs, and IA-2As seroconversions occurred in a cluster (-12 to 8 months) around the ICA seroconversion. We conclude that diabetes-associated autoantibodies emerged in children with predisposing HLA-DQB1 alleles after 3 months of age at a constant tempo, determined by the genetic risk level, usually in the order of IAA, GADA, ICA, and IA-2A. Seroconversion to multiple autoantibody positivity usually occurred tightly clustered in time.
authors.affiliation: Department of Pediatrics, the Juvenile Diabetes Research Foundation Center for Prevention of Type 1 Diabetes in Finland, University of Turku, Turku, Finland. antti.kupila@tyks.fi
authors.forename: Antti
authors.initials: A
authors.lastname: Kupila
authors.forename: Päivi
authors.initials: P
authors.lastname: Keskinen
authors.forename: Tuula
authors.initials: T
authors.lastname: Simell
authors.forename: Satu
authors.initials: S
authors.lastname: Erkkilä
authors.forename: Paula
authors.initials: P
authors.lastname: Arvilommi
authors.forename: Sari
authors.initials: S
authors.lastname: Korhonen
authors.forename: Teija
authors.initials: T
authors.lastname: Kimpimäki
authors.forename: Minna
authors.initials: M
authors.lastname: Sjöroos
authors.forename: Matti
authors.initials: M
authors.lastname: Ronkainen
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000097:blood*; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C096322:ICA512 autoantibody; D007328:Insulin; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2