title: HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients.
abstract: We investigated whether HLA-A*24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D). Persistently Ab(+) siblings/offspring (n = 288; aged 0-39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A*24 and monitored for development of diabetes within 5 years of first Ab(+). HLA-A*24 (P = 0.009), HLA-DQ2/DQ8 (P = 0.001), and positivity for IA-2A ± ZnT8A (P < 0.001) were associated with development of T1D in multivariate analysis. The 5-year risk increased with the number of the above three markers present (n = 0: 6%; n = 1: 18%; n = 2: 46%; n = 3: 100%). Positivity for one or more markers identified a subgroup of 171 (59%) containing 88% of rapid progressors. The combined presence of HLA-A*24 and IA-2A(+) ± ZnT8A(+) defined a subgroup of 18 (6%) with an 82% diabetes risk. Among IA-2A(+) ± ZnT8A(+) relatives, identification of HLA-A*24 carriers in addition to HLA-DQ2/DQ8 carriers increased screening sensitivity for relatives at high Ab- and HLA-inferred risk (64% progression; P = 0.002). In conclusion, HLA-A*24 independently predicts rapid progression to T1D in Ab(+) relatives and complements IA-2A, ZnT8A, and HLA-DQ2/DQ8 for identifying participants in immunointervention trials.
authors.affiliation: Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium. ilse.weets@uzbrussel.be
authors.forename: Eric
authors.initials: E
authors.lastname: Mbunwe
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Van der Auwera
authors.forename: Ilse
authors.initials: I
authors.lastname: Vermeulen
authors.forename: Simke
authors.initials: S
authors.lastname: Demeester
authors.forename: Annelien
authors.initials: A
authors.lastname: Van Dalem
authors.forename: Eric V
authors.initials: EV
authors.lastname: Balti
authors.forename: Sara
authors.initials: S
authors.lastname: Van Aken
authors.forename: Luc
authors.initials: L
authors.lastname: Derdelinckx
authors.forename: Harry
authors.initials: H
authors.lastname: Dorchy
authors.forename: Jean
authors.initials: J
authors.lastname: De Schepper
authors.forename: Chris
authors.initials: C
authors.lastname: van Schravendijk
authors.forename: Janet M
authors.initials: JM
authors.lastname: Wenzlau
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.forename: Daniël
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Ilse
authors.initials: I
authors.lastname: Weets
authors.forename: Frans K
authors.initials: FK
authors.lastname: Gorus
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000097:blood*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D059871:HLA-A24 Antigen / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D059871:HLA-A24 Antigen