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Beyerlein, A. ; Bonifacio, E.* ; Vehik, K.* ; Hippich, M. ; Winkler, C. ; Frohnert, B.I.* ; Steck, A.K.* ; Hagopian, W.A.* ; Krischer, J.P.* ; Lernmark, Å.* ; Rewers, M.J.* ; She, J.X.* ; Toppari, J.* ; Akolkar, B.* ; Rich, S.S.* ; Ziegler, A.-G.

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

J. Med. Genet. 56, 602-605 (2018)

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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.

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