Accelerated Progression to Type 1 Diabetes in the Presence of <i>HLA-A*24</i> and <i>-B*18</i> Is Restricted to Multiple Islet Autoantibody-Positive Individuals With Distinct <i>HLA-DQ</i> and Autoantibody Risk Profiles.

Abstract

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. A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (<i>n</i> = 267) and from multiple-autoantibody positivity to clinical onset (<i>n</i> = 252) according to <i>HLA-DQ</i>, <i>-A*24</i>, <i>-B*18</i>, and <i>-B*39</i> status. Genetic markers were determined by PCR sequence-specific oligotyping. Unlike <i>HLA-B*18</i> or <i>-B*39</i>, <i>HLA-A*24</i> was associated with delayed progression from single- to multiple-autoantibody positivity (<i>P</i> = 0.009) but not to type 1 diabetes. This occurred independently from older age (<i>P</i> < 0.001) and absence of <i>HLA-DQ2/DQ8</i> or <i>-DQ8 (P</i> < 0.001 and <i>P</i> = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, <i>HLA-A*24</i> was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (<i>P</i> = 0.006), but its effects were restricted to <i>HLA-DQ8</i>⁺ relatives with IA-2 or zinc transporter 8 autoantibodies (<i>P</i> = 0.002). <i>HLA-B*18,</i> but not <i>-B*39,</i> was also associated with more rapid progression, but only in <i>HLA-DQ2</i> carriers with double positivity for GAD and insulin autoantibodies (<i>P</i> = 0.004). <i>HLA-A*24</i> predisposes to a delayed antigen spreading of humoral autoimmunity, whereas <i>HLA-A*24</i> and <i>-B*18</i> 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.