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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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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.

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Abbreviations

Ab:

Autoantibody

Ab+ :

Autoantibody-positive

BDR:

Belgian Diabetes Registry

FDRs:

First-degree relatives

GADA:

GAD autoantibodies

IAA:

Insulin autoantibodies

IA-2:

Islet antigen-2

IA-2A:

IA-2 autoantibodies

IQR:

Interquartile range

ZnT8:

Zinc transporter 8

ZnT8A:

ZnT8 autoantibodies

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Acknowledgements

The authors gratefully acknowledge the expert technical assistance of co-workers at the central unit of the Belgian Diabetes Registry (P. Goubert, C. Groven) and the reference laboratory of the Belgian Diabetes Registry (BDR) (V. Baeten, T. De Mesmaeker, H. Dewinter, N. Diependaele, S. Exterbille, T. Glorieux, T. Haulet, A. Ivens, D. Kesler, F. Lebleu, M. Van Molle, S. Vanderstraeten, K. Verhaeghen and A. Walgrave from the Department of Clinical Chemistry and Radio-immunology, University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium; and G. De Block, E. Quartier, G. Schoonjans from the Brussels Free University-VUB, Brussels). The authors also thank the various university teams of co-workers for their excellent assistance in collecting samples and organising the fieldwork: L. Van Gaal, C. De Block, R. Braspenning, J. Michiels, J. Van Elven and J. Vertommen from the University Hospital Antwerp, Antwerp, Belgium; B. Keymeulen, K. Decochez, E. Vandemeulebroucke, U. Van de Velde from the University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium; J. M. Kaufman, J. Ruige, A. Hutse, A. Rawoens and N. Steyaert from the University Hospital Ghent, Ghent, Belgium; and C. Mathieu, P. Gillard, M. Carpentier, M. Robijn, K. Rouffe, A. Schoonis and H. Morobé from the University Hospital Leuven, Leuven, Belgium. The authors sincerely thank all members of the BDR who contributed to the recruitment of relatives for the present study (list of names: see ESM Appendix).

Funding

The present work was supported by grants from the JDRF, Center Grant 4-2005-1327, the European Union (FP-7 project no. 241833), the Belgian Fund for Scientific Research (FWO Vlaanderen projects G.0319.01, G.0514.04, G.0311.07, G.0374.08 and G.0868.11; senior clinical research fellowships to I. Weets, K. Decochez and B. Keymeulen), the Research Council of the Brussels Free University (research fellowship to E. Mbunwe) and the Willy Gepts Fund (projects 3–2005 and 3/22-2007; University Hospital Brussels-UZ Brussel). J. C. Hutton received funding from DERC (NIH P30 DK57516), NIH R01 DK052068 and JDRF 4-2007-1056. The BDR was sponsored by the Belgian National Lottery, the ministries of Public Health of the Flemish and French Communities of Belgium, Hippo & Friends, WeightWatchers, Ortho-Clinical Diagnostics, Novo Nordisk Pharma, Lifescan, Roche Diagnostics, Bayer and Eli Lilly.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors contributed to the design of the study, acquisition of data, statistical analysis, discussion and/or revision of the manuscript. All authors approved the final version.

Author information

Authors and Affiliations

  1. Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, 1090, Brussels, Belgium

    E. Mbunwe, B. J. Van der Auwera, I. Weets, K. Decochez, E. Vandemeulebroucke, B. Keymeulen, C. van Schravendijk, D. G. Pipeleers & F. K. Gorus

  2. Department of Clinical Chemistry and Radio-immunology, University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium

    I. Weets & F. K. Gorus

  3. Department of Endocrinology, OLV-Ziekenhuis, Aalst, Belgium

    P. Van Crombrugge

  4. Department of Endocrinology, ULB-Erasme Hospital, Brussels, Belgium

    L. Crenier

  5. Department of Diabetology, Paola Kinderziekenhuis, Antwerp, Belgium

    M. Coeckelberghs

  6. Department of Pediatrics, CHC Clinique Saint-Joseph, Liège, Belgium

    N. Seret

  7. Department of Diabetology, University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium

    K. Decochez, E. Vandemeulebroucke & B. Keymeulen

  8. Department of Clinical and Experimental Medicine, University of Leuven-KUL and University Hospitals, Leuven, Belgium

    P. Gillard

  9. Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, CO, USA

    J. M. Wenzlau & J. C. Hutton

Authors
  1. E. Mbunwe
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  2. B. J. Van der Auwera
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  3. I. Weets
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  4. P. Van Crombrugge
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  7. N. Seret
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  8. K. Decochez
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  9. E. Vandemeulebroucke
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  10. P. Gillard
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  12. C. van Schravendijk
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  13. J. M. Wenzlau
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  14. J. C. Hutton
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  15. D. G. Pipeleers
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  16. F. K. Gorus
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Consortia

The Belgian Diabetes Registry

Corresponding author

Correspondence to I. Weets.

Additional information

A list of members of the Belgian Diabetes Registry is given in the ESM Appendix

We dedicate this paper to the memory of J. C. Hutton who passed away on December 18, 2012. He contributed to the design of the study, the discussion of the results and the first version of the manuscript

Electronic supplementary material

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ESM Appendix

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ESM Fig. 1

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ESM Table 1

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ESM Table 2

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ESM Table 3

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ESM Table 4

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ESM Table 5

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ESM Table 6

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Mbunwe, E., Van der Auwera, B.J., Weets, I. 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. Diabetologia 56, 1964–1970 (2013). https://doi.org/10.1007/s00125-013-2951-8

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