Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity

Pediatr Diabetes. 2018 Mar;19(2):284-292. doi: 10.1111/pedi.12545. Epub 2017 Jun 9.

Abstract

Objective: The relationship between patterns of islet autoantibodies at diagnosis and specificity of the first islet autoantibody at the initiation of autoimmunity was analyzed with the aim of identifying patterns informative of the primary autoantibodies.

Methods: Information about a single first autoantibody at seroconversion and autoantibody data at diagnosis were available for 128 children participating in the follow-up cohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Autoantibody data at diagnosis and genotyping results were also obtained from children in the Finnish Pediatric Diabetes Register (FPDR).

Results: Insulin autoantibodies (IAA) were the most common primary antibodies (N = 68), followed by those for glutamic acid decarboxylase (GADA; N = 38), IA-2 antigen (IA-2A; N = 13), and zinc transporter 8 (ZnT8A; N = 9), whereas at diagnosis, IA-2A were most frequent (N = 103), followed by IAA (N = 78), ZnT8A (N = 73), and GADA (N = 71). Accordingly, the presence of many specific autoantibodies at diagnosis was due to the secondary antibodies appearing after primary antibodies, and in some cases, the primary autoantibody, most often IAA, had already disappeared at the time of diagnosis. Many of the autoantibody combinations present at diagnosis could be assembled into groups associated with either IAA or GADA as first autoantibodies. These combinations, in children diagnosed below the age of 10 years in the FPDR, were found to be strongly associated with risk genotypes in either INS (IAA first) or IKZF4-ERBB3 (GADA first) genes.

Conclusions: Autoantibody patterns at diagnosis may be informative on primary autoantibodies initiating autoimmunity in young children developing type 1 diabetes.

Keywords: disease heterogeneity; genetics; islet autoantibodies; type 1 diabetes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / analysis*
  • Autoimmunity*
  • Biomarkers / blood
  • Cohort Studies
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / diagnosis*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Family Health
  • Female
  • Finland
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / antagonists & inhibitors
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Ikaros Transcription Factor / antagonists & inhibitors
  • Ikaros Transcription Factor / metabolism
  • Infant, Newborn
  • Insulin / chemistry
  • Insulin / metabolism
  • Kaplan-Meier Estimate
  • Male
  • Polymorphism, Single Nucleotide
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / metabolism
  • Registries
  • Seroconversion*
  • Zinc Transporter 8 / antagonists & inhibitors
  • Zinc Transporter 8 / metabolism

Substances

  • Autoantibodies
  • Biomarkers
  • ICA512 autoantibody
  • IKZF4 protein, human
  • Insulin
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Ikaros Transcription Factor
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • Glutamate Decarboxylase