HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients

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.

FIG. 1.

Diabetes-free survival in persistently Ab⁺ FDRs at baseline (n = 288) stratified according to HLA-A*24, HLA-DQ2/DQ8, and IA-2A/ZnT8A status: presence of HLA-A*24, solid orange line; absence of HLA-A*24, broken orange line (A); presence of HLA-DQ2/DQ8, solid green line; absence of HLA-DQ2/DQ8, broken green line (B); presence of IA-2A and/or ZnT8A, solid purple line; absence of IA-2A and ZnT8A, broken purple line (C); presence of HLA-A*24 and HLA-DQ2/DQ8, solid red line; presence of HLA-DQ2/DQ8 and absence of HLA-A*24, solid green line; presence of HLA-A*24 and absence of HLA-DQ2/DQ8, broken red line; absence of HLA-DQ2/DQ8 and of HLA-A*24, broken green line (D); presence of HLA-A*24 and (IA-2A and/or ZnT8A), solid blue line; presence of (IA-2A and/or ZnT8A) and absence of HLA-A*24, solid yellow line; presence of HLA-A*24 and absence of (IA-2A and ZnT8A), broken blue line; absence of IA-2A, ZnT8A and of HLA-A*24, broken yellow line (E); presence of IA-2A and/or ZnT8A and HLA-DQ2/DQ8, solid fuchsia line; presence of IA-2A and/or ZnT8A and absence of HLA-DQ2/DQ8, solid cyan line; presence of HLA-DQ2/DQ8 and absence of IA-2A and ZnT8A, broken fuchsia line; absence of IA-2A, ZnT8A, and HLA-DQ2/DQ8, broken cyan line (F). The numbers in each panel indicate the number of events for each arm (total number at study entry). P by log-rank test.