title: In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.
abstract: OBJECTIVE
  Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia.
  
  
  METHODS
  A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years.
  
  
  RESULTS
  Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk.
  
  
  CONCLUSIONS
  These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Mbunwe
authors.forename: B J
authors.initials: BJ
authors.lastname: Van der Auwera
authors.forename: I
authors.initials: I
authors.lastname: Weets
authors.forename: P
authors.initials: P
authors.lastname: Van Crombrugge
authors.forename: L
authors.initials: L
authors.lastname: Crenier
authors.forename: M
authors.initials: M
authors.lastname: Coeckelberghs
authors.forename: N
authors.initials: N
authors.lastname: Seret
authors.forename: K
authors.initials: K
authors.lastname: Decochez
authors.forename: E
authors.initials: E
authors.lastname: Vandemeulebroucke
authors.forename: P
authors.initials: P
authors.lastname: Gillard
authors.forename: B
authors.initials: B
authors.lastname: Keymeulen
authors.forename: C
authors.initials: C
authors.lastname: van Schravendijk
authors.forename: J M
authors.initials: JM
authors.lastname: Wenzlau
authors.forename: J C
authors.initials: JC
authors.lastname: Hutton
authors.forename: D G
authors.initials: DG
authors.lastname: Pipeleers
authors.forename: F K
authors.initials: FK
authors.lastname: Gorus
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology*; D005260:Female; D059871:HLA-A24 Antigen / Q000235:genetics*; D059911:HLA-B18 Antigen / Q000235:genetics*; D059946:HLA-B39 Antigen / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D059871:HLA-A24 Antigen; D059911:HLA-B18 Antigen; D059946:HLA-B39 Antigen; D006683:HLA-DQ Antigens