Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study.

Abstract

BACKGROUND:

Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.

METHODS:

In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.

RESULTS:

Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).

CONCLUSIONS:

Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

• Authors: Andreas Beyerlein, Ezio Bonifacio, Kendra Vehik, Markus Hippich, Christiane Winkler, Brigitte I Frohnert, Andrea K Steck, William A Hagopian, Jeffrey P Krischer, Åke Lernmark, Marian J Rewers, Jin-Xiong She, Jorma Toppari, Beena Akolkar, Stephen S Rich, Anette-G Ziegler, TEDDY Study Group
• Journal: Journal of medical genetics (J Med Genet) Vol. 56 Issue 9 Pg. 602-605 (09 2019) ISSN: 1468-6244 [Electronic] England
• PMID: 30287597 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Autoantibodies

Topics

• Autoantibodies (immunology)
• Autoimmunity
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1 (genetics, immunology, pathology)
• Disease Progression
• Female
• Genetic Predisposition to Disease
• Humans
• Infant
• Islets of Langerhans (immunology, metabolism, pathology)
• Male
• Prospective Studies
• Risk Assessment
• Risk Factors