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

Abstract

We investigated whether islet autoantibody profile, <i>HLA-DQ</i> 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. Persistently islet autoAb⁺ siblings and offspring (<i>n</i> = 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. The 20-year progression rate of multiple-autoAb⁺ relatives (<i>n</i> = 194) was higher than that for single-autoAb⁺ participants (<i>n</i> = 268) (88% vs. 54%; <i>P</i> < 0.001). Relatives positive for IAA and GADA (<i>n</i> = 54) progressed more slowly than double-autoAb⁺ individuals carrying IA-2A and/or ZnT8A (<i>n</i> = 38; <i>P</i> = 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 (<i>P</i> < 0.001); in single-autoAb⁺ relatives, it identified younger age (<i>P</i> < 0.001), <i>HLA-DQ2/DQ8</i> genotype (<i>P</i> < 0.001), and IAA (<i>P</i> = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (<i>P</i> = 0.042), <i>HLA-DQ2/DQ8</i> genotype (<i>P</i> = 0.009), and the development of additional autoAbs (<i>P</i> = 0.012) were associated with more rapid progression to diabetes. In single-autoAb⁺ relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and <i>HLA-DQ2/DQ8</i> 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, <i>HLA-DQ</i> genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.