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Genetics/Genomes/Proteomics/Metabolomics

The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History on the Progression From Multiple Autoantibodies to Type 1 Diabetes: A TEDDY Study Report

  1. Jeffrey P. Krischer1⇑,
  2. Xiang Liu1,
  3. Åke Lernmark2,
  4. William A. Hagopian3,
  5. Marian J. Rewers4,
  6. Jin-Xiong She5,
  7. Jorma Toppari6,7,
  8. Anette-G. Ziegler8 and
  9. Beena Akolkar9
  10. on behalf of the TEDDY Study Group*
  1. 1Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
  2. 2Department of Clinical Sciences, Lund University Clinical Research Center, Skåne University Hospital, Malmö, Sweden
  3. 3Pacific Northwest Diabetes Research Institute, Seattle, WA
  4. 4Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO
  5. 5Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA
  6. 6Department of Pediatrics, Turku University Hospital, Turku, Finland
  7. 7Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
  8. 8Institute of Diabetes Research, Helmholtz Zentrum München; Klinikum rechts der Isar, Technische Universität München; and Forschergruppe Diabetes e.V., Neuherberg, Germany
  9. 9National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
  1. Corresponding author: Jeffrey P. Krischer, jeffrey.krischer{at}epi.usf.edu.
Diabetes 2017 Dec; 66(12): 3122-3129. https://doi.org/10.2337/db17-0261
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    Figure 1

    Progression from multiple autoantibodies to T1D by FDR status (P = 0.39 from Cox regression).

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    Figure 2

    Progression from multiple autoantibodies to T1D by HLA-DR-DQ genotypes (P = 0.74 from Cox regression). FDR-specific HLA-DR-DQ genotypes are DR4/4b, DR4/1, DR4/13, DR4/9, and DR3/9.

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    Figure 3

    Progression from multiple autoantibodies to T1D by type of first autoantibody (Ab) (P = 0.02 from Cox regression).

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    Figure 4

    Progression from multiple autoantibodies to T1D by sex (P = 0.03 from Cox regression).

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    Figure 5

    Progression from multiple autoantibodies by number of minor alleles of SNPs within panels rs10517086_A (P = 0.03 from Cox regression) (A), rs1004446_A (P = 0.006 from Cox regression) (B), rs1534422_G (P = 0.006 from Cox regression) (C), and rs2327832_G (P = 0.03 from Cox regression) (D).

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    Figure 6

    Progression from multiple autoantibodies to T1D by number of minor alleles of SNP rs2327832_G in the subset of more than one autoantibody as first-appearing autoantibody (P < 0.001 from Cox regression).

Tables

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  • Table 1

    Characteristics of children who progressed from multiple autoantibodies to T1D and those who did not

    Did not progress to T1DProgressed to T1D
    Total, n (%)222 (54)190 (46)
    Country of residence, n (%)
     U.S.82 (59)57 (41)
     Finland53 (48)57 (52)
     Germany16 (44)20 (56)
     Sweden71 (56)56 (44)
    Family history of T1D, n (%)
     GP171 (55)140 (45)
     FDR: mother12 (50)12 (50)
     FDR: father27 (50)27 (50)
     FDR: sibling12 (52)11 (48)
    Sex, n (%)
     Female88 (49)92 (51)
     Male134 (58)98 (42)
    HLA-DR-DQ genotypes, n (%)
     DR3/4121 (52)110 (48)
     DR4/446 (61)30 (39)
     DR4/831 (56)24 (44)
     DR3/316 (53)14 (47)
     FDR specific8 (40)12 (60)
    Age at multiple persistent confirmed IA (months), median (IQR)48 (31–74)21 (15–31)
    Type of first autoantibody, n (%)
     GADA only85 (66)43 (34)
     IAA only84 (53)76 (47)
     Two or more autoantibodies49 (42)68 (58)
     IA-2A only4 (57)3 (43)
    • FDR-specific HLA-DR-DQ genotypes are DR4/4b, DR4/1, DR4/13, DR4/9, and DR3/9.

  • Table 2

    Cox regression analysis of risk factors for progression from multiple autoantibodies to T1D

    HR (95% CI)P
    Age at multiple autoantibodies onset (months)0.96 (0.95, 0.97)<0.001
    HLA-DR-DQ genotype0.74
     DR3/41.24 (0.79, 1.93)0.35
     DR4/41 [Reference]
     DR4/81.22 (0.68, 2.18)0.50
     DR3/31.44 (0.70, 2.96)0.32
     FDR specific1.58 (0.73, 3.41)0.25
    Family history of T1D0.69
     FDR: mother1.34 (0.66, 2.75)0.42
     FDR: father1.30 (0.80, 2.09)0.29
     FDR: sibling0.98 (0.48, 2.01)0.96
     GP1 [Reference]
    Type of first autoantibody0.02
     GADA only1.16 (0.76, 1.78)0.49
     IAA only1 [Reference]
     Two or more autoantibodies1.66 (1.15, 2.39)0.006
    Sex
     Female1.43 (1.04, 1.96)0.03
     Male1 [Reference]
    Country of residence0.84
     U.S.1 [Reference]
     Finland1.05 (0.53, 2.10)0.89
     Germany1.13 (0.59, 2.14)0.71
     Sweden0.88 (0.58, 1.34)0.55
    SNP rs1004446_A (INS)0.71 (0.55, 0.91)0.006
    SNP rs10517086_A1.31 (1.03, 1.67)0.03
    SNP rs1534422_G1.39 (1.10, 1.76)0.006
    SNP rs2327832_G (TNFAIP3)1.34 (1.03, 1.74)0.03
    PC11.11 (0.91, 1.35)0.32
    PC20.96 (0.72, 1.28)0.78
    • The top two principal components (PC1 and PC2) from the principal components analysis on Immunochip data were included as covariates to correct for population stratification. FDR-specific HLA-DR-DQ genotypes are DR4/4b, DR4/1, DR4/13, DR4/9, and DR3/9.

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The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History on the Progression From Multiple Autoantibodies to Type 1 Diabetes: A TEDDY Study Report
Jeffrey P. Krischer, Xiang Liu, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar
Diabetes Dec 2017, 66 (12) 3122-3129; DOI: 10.2337/db17-0261

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The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History on the Progression From Multiple Autoantibodies to Type 1 Diabetes: A TEDDY Study Report
Jeffrey P. Krischer, Xiang Liu, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar
Diabetes Dec 2017, 66 (12) 3122-3129; DOI: 10.2337/db17-0261
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