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

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.

• Authors: E Mbunwe, B J Van der Auwera, I Weets, P Van Crombrugge, L Crenier, M Coeckelberghs, N Seret, K Decochez, E Vandemeulebroucke, P Gillard, B Keymeulen, C van Schravendijk, J M Wenzlau, J C Hutton, D G Pipeleers, F K Gorus, Belgian Diabetes Registry
• Journal: Diabetologia (Diabetologia) Vol. 56 Issue 9 Pg. 1964-70 (Sep 2013) ISSN: 1432-0428 [Electronic] Germany
• PMID: 23712485 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• HLA-A24 Antigen
• HLA-B18 Antigen
• HLA-B39 Antigen
• HLA-DQ Antigens

Topics

• Adolescent
• Adult
• Autoantibodies (immunology)
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (diagnosis, genetics, immunology)
• Female
• HLA-A24 Antigen (genetics)
• HLA-B18 Antigen (genetics)
• HLA-B39 Antigen (genetics)
• HLA-DQ Antigens (genetics)
• Humans
• Infant
• Infant, Newborn
• Male
• Risk Assessment
• Young Adult