title: Familial clustering of beta-cell autoimmunity in initially non-diabetic children.
abstract: BACKGROUND
  Type 1 diabetes is characterised by familial aggregation. We set out to explore whether beta-cell autoimmunity, which is considered to precede clinical disease, also shows familial clustering.
  
  
  METHODS
  Tests for HLA DQB1 alleles (*02, *0301, *0302, *0602) and islet cell autoantibodies (ICA) were performed on 5836 children from 2283 families. When a child tested positive for ICA, all his/her previous or subsequent samples that were available were also tested for insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GADA) and antibodies to the IA-2 protein (IA-2A).
  
  
  RESULTS
  Forty-four families were observed to have two or more children positive for at least ICA. This proportion (1.9%) was almost five times higher than expected (0.4%; p < 0.001). The frequency of multiple (>/=2) autoantibodies also showed familial aggregation, the observed proportion (0.39%) being three times that expected (0.13%; p < 0.001). In 72.7% of the families with at least two ICA-positive siblings, the children with autoantibodies had the same HLA DQB1 genotype. The median age difference between the ICA-positive children within the same family was 3.3 years (range 0.0-10.5 years), and the median time interval in the appearance of ICA within the family was 1.6 years (range 0.0-3.2).
  
  
  CONCLUSIONS
  beta-cell autoimmunity, as defined by the appearance of ICA, demonstrates familial aggregation, although the antibodies do not appear in close temporal proximity or at an identical age within the same family. The HLA-DQB1 genotypes are more often identical in siblings with autoantibodies than in other siblings.
authors.affiliation: JDRF Centre for the Prevention of Type 1 Diabetes in Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Kukko
authors.forename: Anna
authors.initials: A
authors.lastname: Toivonen
authors.forename: Antti
authors.initials: A
authors.lastname: Kupila
authors.forename: Sari
authors.initials: S
authors.lastname: Korhonen
authors.forename: Päivi
authors.initials: P
authors.lastname: Keskinen
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Suvi M
authors.initials: SM
authors.lastname: Virtanen
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D015551:Autoimmunity / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; 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*; D008297:Male
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007328:Insulin; D005968:Glutamate Decarboxylase