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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

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Mbunwe, E Van der Auwera, B J Weets, I Van Crombrugge, P Crenier, L Van De Poel, Gaëlle [MGD] Lysy, Philippe [UCL] Maes, Marc [UCL]

AIMS/HYPOTHESIS: 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/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2013
Language Anglais
Journal information "Diabetologia : clinical and experimental diabetes and metabolism" - Vol. 56, no. 9, p. 1964-1970 (2013)
Peer reviewed yes
Publisher Springer Verlag ((Germany) Berlin)
issn 0012-186X
e-issn 1432-0428
Publication status Publié
Affiliations UCL - (SLuc) Service d'endocrinologie et diabétologie pédiatrique
UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
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Bibliographic reference Mbunwe, E ; Van der Auwera, B J ; Weets, I ; Van Crombrugge, P ; Crenier, L ; et. al. 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. In: Diabetologia : clinical and experimental diabetes and metabolism, Vol. 56, no. 9, p. 1964-1970 (2013)
Permanent URL http://hdl.handle.net/2078.1/143934