Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes

J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1510-e1517. doi: 10.1210/clinem/dgab853.


Objective: Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes.

Methods: We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses.

Results: Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05).

Conclusions: ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

Trial registration: NCT00097292.

Keywords: HLA genotyping; autoantibody; electrochemiluminescence assay; epidemiology; genetics; prediction; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1* / diagnosis
  • Female
  • Glutamate Decarboxylase
  • HLA Antigens / genetics
  • HLA-DR3 Antigen / genetics
  • HLA-DR4 Antigen / genetics
  • Haplotypes
  • Humans
  • Insulin Antibodies
  • Male
  • Young Adult


  • Autoantibodies
  • HLA Antigens
  • HLA-DR3 Antigen
  • HLA-DR4 Antigen
  • Insulin Antibodies
  • Glutamate Decarboxylase

Associated data