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.

Attenuated humoral responses in HLA-A*24-positive individuals at risk of type 1 diabetes

“…Similarly, as many ENDIT participants were adults, only a minority had IAA and this may have limited our ability to identify subtle effects of HLA-A*24 on IAA prevalence and levels [10]. In contrast with other studies of at-risk relatives [2], we did not observe accelerated progression in HLA-A*24-positive ENDIT participants. The individuals at highest risk, including HLA-A*24 carriers, may have developed diabetes between ICA screening and study entry.…”

“…The rate of beta cell destruction is heterogeneous among multiple islet autoantibody-positive individuals, but the reasons for this are poorly defined. The main type 1 diabetes susceptibility alleles are in the HLA class II region, but the class I allele HLA-A*24 has been linked with accelerated diabetes progression, acute diabetes onset and early and complete beta cell destruction [2]. Islet autoantibody characteristics in HLA-A*24 individuals with diabetes have proved counterintuitive; one might expect an overwhelming islet autoantibody response to be associated with rapid progression, but the opposite appears true.…”

HLA-A*24Carrier Status and Autoantibody Surges Posttransplantation Associate With Poor Functional Outcome in Recipients of an Islet Allograft

“…The current results indicate that similar to observations in pre-type 1 diabetes, the presence of HLA-A*24 or autoantibody surges predicts b-cell loss during an inflammatory and/or immune process in islet allograft recipients (7,8). The association of early autoantibody rises with poor graft outcome confirms previous observations and has been explained as the consequence of autoantigen release after b-cell death (12).…”

“…Assays were validated by participation in successive Diabetes Antibody Standardization Programs (10). HLA-DQ2/DQ8 and -A*24 were determined by allele-specific oligotyping (8). The hyperglycemic clamp procedure was performed as previously described (6).…”

“…However, a positive outcome can be counteracted by other factors, including preexisting autoreactive T cells, HLA alloantibodies, or high lymphocyte counts (2-4). In recipients of a sufficiently large intraportal islet allograft (5,6), we investigated whether the presence of HLA-A*24, HLA-DQ2/DQ8, or rising islet autoantibody levels, previously shown to independently predict rapid b-cell loss in prediabetes (7,8), associates with poor functional graft outcome. …”