title: Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes.
abstract: OBJECTIVE
  To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA).
  
  
  METHODS
  We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA).
  
  
  RESULTS
  ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 1-3 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (p < 0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2).
  
  
  CONCLUSIONS
  Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden. Cecilia_K.Andersson@med.lu.se
authors.forename: C
authors.initials: C
authors.lastname: Andersson
authors.forename: F
authors.initials: F
authors.lastname: Vaziri-Sani
authors.forename: Aj
authors.initials: A
authors.lastname: Delli
authors.forename: B
authors.initials: B
authors.lastname: Lindblad
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: G
authors.initials: G
authors.lastname: Forsander
authors.forename: J
authors.initials: J
authors.lastname: Ludvigsson
authors.forename: C
authors.initials: C
authors.lastname: Marcus
authors.forename: U
authors.initials: U
authors.lastname: Samuelsson
authors.forename: Sa
authors.initials: S
authors.lastname: Ivarsson
authors.forename: A
authors.initials: A
authors.lastname: Lernmark
authors.forename: H Elding
authors.initials: HE
authors.lastname: Larsson
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2