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

Genetics/Genomes/Proteomics/Metabolomics

¹Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
²Department of Clinical Sciences, Lund University Clinical Research Center, Skåne University Hospital, Malmö, Sweden
³Pacific Northwest Diabetes Research Institute, Seattle, WA
⁴Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO
⁵Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA
⁶Department of Pediatrics, Turku University Hospital, Turku, Finland
⁷Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
⁸Institute of Diabetes Research, Helmholtz Zentrum München; Klinikum rechts der Isar, Technische Universität München; and Forschergruppe Diabetes e.V., Neuherberg, Germany
⁹National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD

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).

Table 1

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

	Did not progress to T1D	Progressed to T1D
Total, n (%)	222 (54)	190 (46)
Country of residence, n (%)
U.S.	82 (59)	57 (41)
Finland	53 (48)	57 (52)
Germany	16 (44)	20 (56)
Sweden	71 (56)	56 (44)
Family history of T1D, n (%)
GP	171 (55)	140 (45)
FDR: mother	12 (50)	12 (50)
FDR: father	27 (50)	27 (50)
FDR: sibling	12 (52)	11 (48)
Sex, n (%)
Female	88 (49)	92 (51)
Male	134 (58)	98 (42)
HLA-DR-DQ genotypes, n (%)
DR3/4	121 (52)	110 (48)
DR4/4	46 (61)	30 (39)
DR4/8	31 (56)	24 (44)
DR3/3	16 (53)	14 (47)
FDR specific	8 (40)	12 (60)
Age at multiple persistent confirmed IA (months), median (IQR)	48 (31–74)	21 (15–31)
Type of first autoantibody, n (%)
GADA only	85 (66)	43 (34)
IAA only	84 (53)	76 (47)
Two or more autoantibodies	49 (42)	68 (58)
IA-2A only	4 (57)	3 (43)

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 genotype		0.74
DR3/4	1.24 (0.79, 1.93)	0.35
DR4/4	1 [Reference]
DR4/8	1.22 (0.68, 2.18)	0.50
DR3/3	1.44 (0.70, 2.96)	0.32
FDR specific	1.58 (0.73, 3.41)	0.25
Family history of T1D		0.69
FDR: mother	1.34 (0.66, 2.75)	0.42
FDR: father	1.30 (0.80, 2.09)	0.29
FDR: sibling	0.98 (0.48, 2.01)	0.96
GP	1 [Reference]
Type of first autoantibody		0.02
GADA only	1.16 (0.76, 1.78)	0.49
IAA only	1 [Reference]
Two or more autoantibodies	1.66 (1.15, 2.39)	0.006
Sex
Female	1.43 (1.04, 1.96)	0.03
Male	1 [Reference]
Country of residence		0.84
U.S.	1 [Reference]
Finland	1.05 (0.53, 2.10)	0.89
Germany	1.13 (0.59, 2.14)	0.71
Sweden	0.88 (0.58, 1.34)	0.55
SNP rs1004446_A (INS)	0.71 (0.55, 0.91)	0.006
SNP rs10517086_A	1.31 (1.03, 1.67)	0.03
SNP rs1534422_G	1.39 (1.10, 1.76)	0.006
SNP rs2327832_G (TNFAIP3)	1.34 (1.03, 1.74)	0.03
PC1	1.11 (0.91, 1.35)	0.32
PC2	0.96 (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.