HLA-A*24 Is an Independent Predictor of 5-Year Progression to Diabetes in Autoantibody-Positive First-Degree Relatives of Type 1 Diabetic Patients

  1. Belgian Diabetes Registry*
  1. 1Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium
  2. 2Department of Pediatrics, University Hospital Ghent, Ghent, Belgium
  3. 3Department of Endocrinology, Clinique Saint-Luc, Bouge-Namur, Belgium
  4. 4Diabetology Clinic, University Children's Hospital Queen Fabiola, Free University of Brussels, Brussels, Belgium
  5. 5Department of Pediatrics, University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium
  6. 6Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, Colorado
  7. 7Department of Clinical Chemistry and Radio-immunology, University Hospital Brussels Free University-UZ Brussel, Brussels, Belgium
  1. Corresponding author: Ilse Weets, ilse.weets{at}uzbrussel.be.
  1. E.M. and B.J.V.d.A. contributed equally to this study.

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.

Footnotes

  • * A complete list of the members of the Belgian Diabetes Registry can be found in the appendix.

  • Received June 7, 2012.
  • Accepted September 4, 2012.

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