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.
Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors : Results from the prospective TEDDY study. / Beyerlein, Andreas; Bonifacio, Ezio; Vehik, Kendra; Hippich, Markus; Winkler, Christiane; Frohnert, Brigitte I.; Steck, Andrea K.; Hagopian, William A.; Krischer, Jeffrey P.; Lernmark, Åke; Rewers, Marian J.; She, Jin Xiong; Toppari, Jorma; Akolkar, Beena; Rich, Stephen S.; Ziegler, Anette G.In: Journal of medical genetics, Vol. 56, No. 9, 01.09.2019, p. 602-605.
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