title: Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome.
abstract: OBJECTIVE
  Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes.
  
  
  METHODS
  Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay.
  
  
  RESULTS
  Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort.
  
  
  CONCLUSIONS
  Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.
authors.affiliation: University of Bristol, Bristol, U.K.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Aitken
authors.forename: Kay L
authors.initials: KL
authors.lastname: Mehers
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Williams
authors.forename: Jamie
authors.initials: J
authors.lastname: Brown
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Reinhard W
authors.initials: RW
authors.lastname: Holl
authors.forename: Tilman R
authors.initials: TR
authors.lastname: Rohrer
authors.forename: Edith
authors.initials: E
authors.lastname: Schober
authors.forename: Majedah M
authors.initials: MM
authors.lastname: Abdul-Rasoul
authors.forename: Julian P H
authors.initials: JP
authors.lastname: Shield
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004314:Down Syndrome / Q000235:genetics / Q000276:immunology*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011863:Radioimmunoassay; D055815:Young Adult
chemical_list: D000949:Histocompatibility Antigens Class II