Diabetologia

, Volume 56, Issue 9, pp 1964–1970

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

  • 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
  • The Belgian Diabetes Registry
Article

DOI: 10.1007/s00125-013-2951-8

Cite this article as:
Mbunwe, E., Van der Auwera, B.J., Weets, I. et al. Diabetologia (2013) 56: 1964. doi:10.1007/s00125-013-2951-8

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.

Keywords

AutoantibodiesHLA-AHLA-BHLA class IHLA class IIHLA-DQPredictionPreventionRisk assessmentType 1 diabetes

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

Supplementary material

125_2013_2951_MOESM1_ESM.pdf (21 kb)
ESM Appendix(PDF 21 kb)
125_2013_2951_MOESM2_ESM.pdf (41 kb)
ESM Fig. 1(PDF 41 kb)
125_2013_2951_MOESM3_ESM.pdf (62 kb)
ESM Table 1(PDF 62 kb)
125_2013_2951_MOESM4_ESM.pdf (48 kb)
ESM Table 2(PDF 47 kb)
125_2013_2951_MOESM5_ESM.pdf (51 kb)
ESM Table 3(PDF 51 kb)
125_2013_2951_MOESM6_ESM.pdf (69 kb)
ESM Table 4(PDF 69 kb)
125_2013_2951_MOESM7_ESM.pdf (63 kb)
ESM Table 5(PDF 62 kb)
125_2013_2951_MOESM8_ESM.pdf (60 kb)
ESM Table 6(PDF 60 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • E. Mbunwe
    • 1
  • B. J. Van der Auwera
    • 1
  • I. Weets
    • 1
    • 2
  • P. Van Crombrugge
    • 3
  • L. Crenier
    • 4
  • M. Coeckelberghs
    • 5
  • N. Seret
    • 6
  • K. Decochez
    • 1
    • 7
  • E. Vandemeulebroucke
    • 1
    • 7
  • P. Gillard
    • 8
  • B. Keymeulen
    • 1
    • 7
  • C. van Schravendijk
    • 1
  • J. M. Wenzlau
    • 9
  • J. C. Hutton
    • 9
  • D. G. Pipeleers
    • 1
  • F. K. Gorus
    • 1
    • 2
  • The Belgian Diabetes Registry
    • 10
  1. 1.Diabetes Research CenterBrussels Free University-VUBBrusselsBelgium
  2. 2.Department of Clinical Chemistry and Radio-immunologyUniversity Hospital Brussels Free University-UZ BrusselBrusselsBelgium
  3. 3.Department of EndocrinologyOLV-ZiekenhuisAalstBelgium
  4. 4.Department of EndocrinologyULB-Erasme HospitalBrusselsBelgium
  5. 5.Department of DiabetologyPaola KinderziekenhuisAntwerpBelgium
  6. 6.Department of PediatricsCHC Clinique Saint-JosephLiègeBelgium
  7. 7.Department of DiabetologyUniversity Hospital Brussels Free University-UZ BrusselBrusselsBelgium
  8. 8.Department of Clinical and Experimental MedicineUniversity of Leuven-KUL and University HospitalsLeuvenBelgium
  9. 9.Barbara Davis Center for Childhood DiabetesUniversity of Colorado at DenverAuroraUSA
  10. 10.BrusselsBelgium