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 distinct HLA-DQ interactions

Abstract

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 0-39 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 < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). 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 ≥ 3 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.

Figure 1. Diabetes-free survival according to HLA-B*18, HLA-B*39 or HLA-A*24 status in 288 persistently Ab⁺ FDRs with or without stratification according to the presence or absence of HLA-DQ8 or HLA-DQ2

(a) Whole group (n = 288) with (solid line) vs without (dashed line) HLA-B*18 (p = 0.021). (b) Whole group (n = 288) with (solid line) vs without (dashed line) HLA-B*39 (p = 0.377). (c) HLA-DQ8-positive (n = 174) relatives with (solid line) vs without (dashed line) HLA-A*24 (p = 0.002). (d) HLA-DQ8-negative relatives (n = 114) with (solid line) vs without (dashed line) HLA-A*24 (p = 0.750). (e) HLA-DQ2-positive (n = 145) relatives with (solid line) vs without (dashed line) HLA-B*18 (p = 0.005). (f) HLA-DQ2-negative relatives (n = 143) with (solid line) vs without (dashed line) HLA-B*18 (p = 0.277). The numbers given for each arm are number of events (total number at study entry). For the number of relatives under follow-up at different time points, see ESM Table 3. p by logrank test.

Figure 2

Diabetes-free survival in 246 persistently Ab⁺ FDRs carrying HLA-DQ2 and/or HLA-DQ8 according to (a) presence (solid line) vs absence (dashed line) of HLA-B*18 (p = 0.010) or (b) presence of at least three of four markers (solid line) vs two of four markers (dashed line) vs one of four markers (dotted/dashed line) vs absence of all four markers (dotted line) (overall p < 0.001). Markers are independent predictors of 5 year diabetes risk in HLA-DQ2- and/or HLA-DQ8-positive relatives (positive for IA-2A and/or ZnT8A, HLA-DQ2/DQ8, HLA-A*24 and HLA-B*18). The numbers given for each arm are number of events (total number at study entry). p by logrank test.