PT - JOURNAL ARTICLE AU - Beyerlein, Andreas AU - Bonifacio, Ezio AU - Vehik, Kendra AU - Hippich, Markus AU - Winkler, Christiane AU - Frohnert, Brigitte I AU - Steck, Andrea K AU - Hagopian, William A AU - Krischer, Jeffrey P AU - Lernmark, Åke AU - Rewers, Marian J AU - She, Jin-Xiong AU - Toppari, Jorma AU - Akolkar, Beena AU - Rich, Stephen S AU - Ziegler, Anette-G ED - TI - Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study AID - 10.1136/jmedgenet-2018-105532 DP - 2019 Sep 01 TA - Journal of Medical Genetics PG - 602--605 VI - 56 IP - 9 4099 - http://jmg.bmj.com/content/56/9/602.short 4100 - http://jmg.bmj.com/content/56/9/602.full SO - J Med Genet2019 Sep 01; 56 AB - 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.