TY - JOUR
T1 - Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors
T2 - Results from the prospective TEDDY study
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.
N1 - Funding Information:
Funding this study was funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955 and contract no hhSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child health and human Development (NIChD), National Institute of environmental health Sciences (NIehS), Juvenile Diabetes research Foundation (JDrF), and the Centers for Disease Control and prevention (CDC). this work was supported in part by the NIh/NCAtS Clinical and translational Science Awards to the University of Florida (UL1 tr000064) and the University of Colorado (UL1 tr001082).
Funding Information:
This study was funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955 and contract no HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and the Centers for Disease Control and Prevention (CDC). This work was supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082).
Publisher 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.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
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.
KW - diabetes
KW - diagnostics tests
KW - epidemiology
KW - immunology (including allergy)
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U2 - 10.1136/jmedgenet-2018-105532
DO - 10.1136/jmedgenet-2018-105532
M3 - Article
C2 - 30287597
AN - SCOPUS:85054379240
VL - 56
SP - 602
EP - 605
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 9
ER -