Immunogenetic–metabolic profiles in clinically healthy siblings of patients with type 1 diabetes

BACKGROUND: Clinically healthy siblings of patients with type 1 diabetes (T1D) exhibit immunogenetic and metabolic heterogeneity, which limits the accuracy of individual risk assessment when single markers are used. Integration of HLA risk, islet autoantibody (AAb) status, and metabolic parameters may improve identification of the preclinical stages of T1D.

AIM: To identify immunogenetic-metabolic profiles among clinically healthy siblings of patients with T1D based on the integration of HLA risk, AAb status, and metabolic parameters, and to assess their potential role in characterizing the preclinical stage of the disease.

MATERIALS AND METHODS: This multicenter prospective cohort study included 420 participants: 254 patients with newly diagnosed T1D (aged 0–17 years) and 166 of their healthy siblings. AAb (IAA, GADA, IA-2A, ZnT8A, ICA), glycated hemoglobin (HbA_1c), and C-peptide were measured, and HLA typing of class II loci (HLA-DR and HLA-DQ) was performed. Immunogenetic-metabolic profiles were identified using two-step cluster analysis. Statistical analyses included nonparametric tests, χ² test, logistic regression, ROC analysis, and event-free survival analysis (p < 0.05).

RESULTS: Among the 166 siblings, two-step cluster analysis (silhouette measure 0.49) identified four immunogenetic-metabolic profiles: isolated genetic (21%) — high HLA risk without autoantibodies or metabolic abnormalities; early autoimmune (22%) — ≥1 autoantibody and high HLA risk without significant metabolic changes; metabolic (27%) — absence of autoantibodies, reduced C-peptide, and predominance of low/intermediate HLA risk; and combined (31%) — ≥1 autoantibody, HbA1c ≥5.4% in 100%, reduced C-peptide < 0.54 ng/mL in 24%, and high HLA risk in 59%. During 7.1 years of follow-up, T1D developed in 4.2% of siblings and was numerically more frequent in the combined profile (7.8%) without statistically significant differences . A significant linear trend was observed for increasing frequencies of IA-2A, ZnT8A, and GADA toward T1D onset (p < 0.001). ZnT8A were an independent predictor of belonging to the combined profile. The median number of autoantibody types was higher at T1D onset (3 vs 0; p=0.006). Inclusion of reduced C-peptide was associated with improved discriminative performance of the model (AUC=0.857).

CONCLUSION: Distinct immunogenetic-metabolic profiles were identified in clinically healthy siblings of patients with T1D based on the combination of HLA risk, AAb status, and metabolic parameters. The profile characterized by concurrent autoimmune activity and reduced β-cell functional reserve was characterized by a higher frequency of T1D onset.

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