In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distin
文摘
Aims/hypothesis Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. Methods A registry-based group of 288 persistently autoantibody-positive (Ab+) offspring/siblings (aged 0-9?years) of known patients (Ab+ against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab+ sample for development of diabetes within 5?years. Results Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p-lt;-.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p-lt;-.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n--46), HLA-B*18 predicted impending diabetes (p--.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p?≤-.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p?≤-.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ? risk markers conferring >85% 5 year risk. Conclusions/interpretation These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.