Accelerated progression to Type 1 diabetes in the presence of HLA-A*24 and -B*18 is restricted to multiple-islet autoantibody-positive individuals with distinct HLA-DQ- and autoantibody risk profiles

Else M Balke, Eric V Balti, Bart Van der Auwera, Ilse Weets, Olivier Costa, Simke Demeester, Pascale Abrams, Kristina Casteels, Marina Coeckelberghs, Sylvie Tenoutasse, Bart Keymeulen, Daniel G Pipeleers, Frans K Gorus, Belgian Diabetes Registry

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

OBJECTIVE: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A 24, -B 18, and -B 39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS: Unlike HLA-B 18 or -B 39, HLA-A 24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurredindependently from olderage(P<0.001)and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A 24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8 +relatives with IA-2 or zinctransporter8 autoantibodies (P = 0.002). HLA-B 18, but not -B 39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS: HLA-A 24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A 24 and -B 18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.

Original languageEnglish
Pages (from-to)1076-1083
Number of pages8
JournalDiabetes Care
Volume41
Issue number5
Early online date2018
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • Adolescent
  • Adult
  • Autoantibodies/blood
  • Autoimmunity/genetics
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1/blood
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-A24 Antigen/genetics
  • HLA-B18 Antigen/genetics
  • HLA-DQ Antigens/genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Insulin Antibodies/blood
  • Islets of Langerhans/immunology
  • Male
  • Registries
  • Risk Factors
  • Young Adult

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