TY - JOUR
T1 - Role of type 1 diabetes- Associated snps on risk of autoantibody positivity in the TEDDY study
AU - Törn, Carina
AU - Hadley, David
AU - Lee, Hye Seung
AU - Hagopian, William
AU - Lernmark, Åke
AU - Simell, Olli
AU - Rewers, Marian
AU - Ziegler, Anette
AU - Schatz, Desmond
AU - Akolkar, Beena
AU - Onengut-Gumuscu, Suna
AU - Chen, Wei Min
AU - Toppari, Jorma
AU - Mykkänen, Juha
AU - Ilonen, Jorma
AU - Rich, Stephen S.
AU - She, Jin-Xiong
AU - Steck, Andrea K.
AU - Krischer, Jeffrey
N1 - Funding Information:
Funding. This work 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, and UC4 DK95300 and contract number HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, JDRF, and the 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). The Royal Physiographic Society in Lund, Sweden, contributed with a travel grant to C.T. for participation in the 2013 Immunology of Diabetes Society Meeting. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.T. conceived the study, interpreted data, and wrote the manuscript. D.H. and H.-S.L. analyzed data and reviewed/edited the manuscript. W.H., B.A., and S.S.R. contributed to study design and performance, discussion, and reviewed/edited the manuscript. Å.L., O.S., M.R., A.Z., D.S., and J.K. contributed to study design and performance and discussion. S.O.-G. and W.-M.C. contributed to study performance and discussion. J.T. and J.I. contributed to discussion. J.M. and A.K.S. reviewed/edited the manuscript. J.-X.S. contributed to study design and performance and reviewed/edited the manuscript. D.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the European Association for the Study of Diabetes Study Group for Genetics of Diabetes Meeting, Malmö, Sweden, 3–5 May 2013 (poster presentation) and at the Immunology of Diabetes Society Meeting, Melbourne, Australia, 7–11 December 2013 (oral presentation).
Funding Information:
This work 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, and UC4 DK95300 and contract number HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, JDRF, and the 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). The Royal Physiographic Society in Lund, Sweden, contributed with a travel grant to C.T. for participation in the 2013 Immunology of Diabetes Society Meeting.
PY - 2015/5
Y1 - 2015/5
N2 - The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta- Analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying highrisk HLA genotypes, eight SNPs achieved significant association to development of IA using time- To-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): Rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]), and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: Rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.
AB - The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta- Analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying highrisk HLA genotypes, eight SNPs achieved significant association to development of IA using time- To-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): Rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]), and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: Rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.
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U2 - 10.2337/db14-1497
DO - 10.2337/db14-1497
M3 - Article
C2 - 25422107
AN - SCOPUS:84981556018
SN - 0012-1797
VL - 64
SP - 1818
EP - 1829
JO - Diabetes
JF - Diabetes
IS - 5
ER -
