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Bonifacio, E.; Krumsiek, J.; Winkler, C.; Theis, F. J.; Ziegler, A. G. 
A strategy to find gene combinations that identify children who progress rapidly to type 1 diabetes after islet autoantibody seroconversion 
We recently developed a novel approach capable of identifying gene combinations to obtain maximal disease risk stratification. Type 1 diabetes has a preclinical phase including seroconversion to autoimmunity and subsequent progression to diabetes. Here, we applied our gene combination approach to identify combinations that contribute either to islet autoimmunity or to the progression from islet autoantibodies to diabetes onset. We examined 12 type 1 diabetes susceptibility genes (INS, ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10) in a cohort of children of parents with type 1 diabetes and prospectively followed from birth. The most predictive combination was subsequently applied to a smaller validation cohort. The combinations of genes only marginally contributed to the risk of developing islet autoimmunity, but could substantially modify risk of progression to diabetes in islet autoantibody-positive children. The greatest discrimination was provided by risk allele scores of five genes, INS, IFIH1, IL18RAP, CD25, and IL2 genes, which could identify 80  
Type 1 diabetes Type 1 diabetes susceptibility genes Islet autoimmunity Progression 
Acta Diabetol. 
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