TY - JOUR
T1 - Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort
AU - TEDDY study group
AU - Sharma, Ashok Kumar
AU - Liu, Xiang
AU - Hadley, David
AU - Hagopian, William
AU - Chen, Wei Min
AU - Onengut-Gumuscu, Suna
AU - Törn, Carina
AU - Steck, Andrea K.
AU - Frohnert, Brigitte I.
AU - Rewers, Marian
AU - Ziegler, Anette G.
AU - Lernmark, Åke
AU - Toppari, Jorma
AU - Krischer, Jeffrey P.
AU - Akolkar, Beena
AU - Rich, Stephen S.
AU - She, Jin-Xiong
N1 - Funding Information:
The TEDDY Study is 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 , UC4 DK112243 , UC4 DK117483 , 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), Centers for Disease Control and Prevention (CDC) , and JDRF . This work 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 ).
PY - 2018/5
Y1 - 2018/5
N2 - Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10−7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10−6) and one novel region near PPIL2 (HR = 2.47, p = 9.64 × 10−7) with suggestive evidence (p < 10−5). Two known regions (PTPN22: p = 2.25 × 10−6, INS; p = 1.32 × 10−7) and one novel region (PXK/PDHB: p = 8.99 × 10−6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 × 10−6 and TTC34/PRDM16: 6.45 × 10−6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p = 8.02 × 10−6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 × 10−7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 × 10−6 > p > 2.31 × 10−6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.
AB - Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10−7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10−6) and one novel region near PPIL2 (HR = 2.47, p = 9.64 × 10−7) with suggestive evidence (p < 10−5). Two known regions (PTPN22: p = 2.25 × 10−6, INS; p = 1.32 × 10−7) and one novel region (PXK/PDHB: p = 8.99 × 10−6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 × 10−6 and TTC34/PRDM16: 6.45 × 10−6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p = 8.02 × 10−6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 × 10−7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 × 10−6 > p > 2.31 × 10−6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.
KW - Autoimmune disorder
KW - Gene mapping
KW - Susceptibility
KW - TEDDY study
KW - Type 1 diabetes
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U2 - 10.1016/j.jaut.2017.12.008
DO - 10.1016/j.jaut.2017.12.008
M3 - Article
C2 - 29310926
AN - SCOPUS:85039990378
VL - 89
SP - 90
EP - 100
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -