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

Diabetes Care. 2017 Aug;40(8):1065-1072. doi: 10.2337/dc16-2228.


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

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / blood*
  • Belgium
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / blood*
  • Diabetes Mellitus, Type 1 / genetics
  • Disease Progression*
  • Female
  • Follow-Up Studies
  • HLA-DQ Antigens / genetics*
  • Humans
  • Infant
  • Insulin / blood
  • Male
  • Proportional Hazards Models
  • Registries*
  • Risk Factors
  • Surveys and Questionnaires
  • Young Adult
  • Zinc Transporter 8 / blood


  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • Insulin
  • SLC30A8 protein, human
  • Zinc Transporter 8