Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes.

Objective: We investigated whether islet autoantibody profile, genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb) in first-degree relatives of patients with type 1 diabetes.

Research Design And Methods: Persistently islet autoAb siblings and offspring ( = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay.

Results: The 20-year progression rate of multiple-autoAb relatives ( = 194) was higher than that for single-autoAb participants ( = 268) (88% vs. 54%; < 0.001). Relatives positive for IAA and GADA ( = 54) progressed more slowly than double-autoAb individuals carrying IA-2A and/or ZnT8A ( = 38; = 0.001). In multiple-autoAb relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes ( < 0.001); in single-autoAb relatives, it identified younger age ( < 0.001), genotype ( < 0.001), and IAA ( = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age ( = 0.042), genotype ( = 0.009), and the development of additional autoAbs ( = 0.012) were associated with more rapid progression to diabetes.

Conclusions: In single-autoAb relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and genotype. The majority of multiple-autoAb individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.