Autoantibodies to islet antigen-2 are associated with HLA-DRB1*07 and DRB1*09 haplotypes as well as DRB1*04 at onset of type 1 diabetes: the possible role of HLA-DQA in autoimmunity to IA-2

Diabetologia. 2008 Aug;51(8):1444-8. doi: 10.1007/s00125-008-1047-3. Epub 2008 May 27.


Aims/hypothesis: To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A).

Methods: HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7-20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients.

Results: IA-2A prevalence was highest in patients carrying at least one HLA-DRB1*04-DQA1*0301 (385 of 450; 86%), DRB1*07-DQA1*(0201 or 0301) (58 of 64; 91%) or DRB1*09-DQA1*0301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes (p < 0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB1*03-DQB1*02 or DRB1*07-DQB1*02 haplotypes than in those negative for these haplotypes (52%) (p = 0.002), but showed an independent positive association with IA-2A level (p < 0.001).

Conclusions/interpretation: HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB1*04, DRB1*07 and DRB1*09 alleles in linkage disequilibrium with DQA1*0301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autoantibodies / immunology*
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • HLA-DQ Antigens / immunology*
  • HLA-DQ alpha-Chains
  • HLA-DR Antigens / immunology*
  • HLA-DRB1 Chains
  • Humans
  • Infant
  • Male
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology*


  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04 antigen
  • HLA-DRB1*07 antigen
  • PTPRN protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8