TY - JOUR
T1 - The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history on the progression from multiple autoantibodies to type 1 diabetes
T2 - A teddy study report
AU - Krischer, Jeffrey P.
AU - Liu, Xiang
AU - Lernmark, Åke
AU - Hagopian, William A.
AU - Rewers, Marian J.
AU - She, Jin Xiong
AU - Toppari, Jorma
AU - Ziegler, Anette G.
AU - Akolkar, Beena
N1 - Funding Information:
Acknowledgments. A special acknowledgment to the TEDDY families for their continued participation in this wonderful study. Funding. This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (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, and UC4 DK95300) and by the National Institutes of Health (HHSN267200700014C). This work was also funded by National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, JDRF, and Centers for Disease Control and Prevention. This work was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. All authors attest to meeting the International Committee of Medical Journal Editors uniform requirements for authorship by making substantial contributions to conception and design of this paper; acquisitioning, analyzing, and interpreting the data; drafting or revising the article for intellectual content; and giving final approval of the published version. J.P.K. designed the study, proposed the analysis, interpreted the findings, and wrote the manuscript. X.L. performed the analysis and contributed to the manuscript. Å.L., W.A.H., M.J.R., J.-X.S., J.T., A.-G.Z., and B.A. designed the study and reviewed or edited the manuscript. J.P.K. and X.L. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2017 by the American Diabetes Association.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two ormore diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibodypositive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446-A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA-DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first-appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086-A [P = 0.03], rs1534422-G [P = 0.006], and rs2327832-G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446-A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.
AB - This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two ormore diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibodypositive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446-A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA-DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first-appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086-A [P = 0.03], rs1534422-G [P = 0.006], and rs2327832-G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446-A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.
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U2 - 10.2337/db17-0261
DO - 10.2337/db17-0261
M3 - Article
C2 - 28903990
AN - SCOPUS:85035347149
SN - 0012-1797
VL - 66
SP - 3122
EP - 3129
JO - Diabetes
JF - Diabetes
IS - 12
ER -
