Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families

Markus Hippich; Andreas Beyerlein; William A. Hagopian; Jeffrey P. Krischer; Kendra Vehik; Jan Knoop; Christiane Winker; Jorma Toppari; Åke Lernmark; Marian J. Rewers; Andrea K. Steck; Jin-Xiong She; Beena Akolkar; Catherine C. Robertson; Suna Onengut-Gumuscu; Stephen S. Rich; Ezio Bonifacio; Anette-G. Ziegler; the TEDDY Study Group

doi:10.2337/db18-0882

Genetics/Genomes/Proteomics/Metabolomics

Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families

Markus Hippich¹,
Andreas Beyerlein¹,²,
William A. Hagopian³,
Jeffrey P. Krischer⁴,
Kendra Vehik⁴,
Jan Knoop¹,
Christiane Winker¹,⁵,
Jorma Toppari⁶,
Åke Lernmark⁷,
Marian J. Rewers⁸,
Andrea K. Steck⁸,
Jin-Xiong She⁹,
Beena Akolkar¹⁰,
Catherine C. Robertson¹¹,
Suna Onengut-Gumuscu¹¹,
Stephen S. Rich¹¹,
Ezio Bonifacio⁵,¹² ⇑,
Anette-G. Ziegler¹,²,⁵ ⇑,
the TEDDY Study Group*

¹Institute of Diabetes Research, Helmholtz Zentrum München (German Research Center for Environmental Health), Munich-Neuherberg, Germany
²Forschergruppe Diabetes, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
³Pacific Northwest Research Institute, Seattle, WA
⁴Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
⁵Forschergruppe Diabetes e.V., Helmholtz Zentrum München (German Research Center for Environmental Health), Munich-Neuherberg, Germany
⁶Department of Pediatrics, Turku University Hospital, and Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
⁷Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden
⁸Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO
⁹Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA
¹⁰National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
¹¹Center for Public Health Genomics, University of Virginia, Charlottesville, VA
¹²DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

Corresponding authors: Anette-G. Ziegler, anette-g.ziegler{at}helmholtz-muenchen.de, and Ezio Bonifacio, ezio.bonifacio{at}tu-dresden.de

Diabetes 2019 Apr; 68(4): 847-857. https://doi.org/10.2337/db18-0882

Article Figures & Tables

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Figure 1
Cumulative risks of islet autoantibodies and diabetes. Kaplan-Meier curves for the risk of one or more islet autoantibodies (A and B), multiple islet autoantibodies (C and D), and diabetes (E and F) in FDR children (red) and in GP children (blue), stratified into children with the HLA DR3/DR4-DQ8 (A, C, and E) or HLA DR4-DQ8/DR4-DQ8 (B, D, and F) genotypes. Shaded areas represent the 95% CI. Numbers represent children at risk. P values were calculated using log-rank tests.
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Figure 2
A: Distribution of non-HLA DR-DQ genetic risk scores in all 4,414 DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 children stratified into FDR children (red) and GP children (blue). B: Distribution of non-HLA DR-DQ genetic risk scores in 317 DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 children who developed multiple islet autoantibodies. P values were calculated using the two-sided Mann-Whitney U test.
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Figure 3
The modification of risk by the BTNL2 SNP rs3763305 on the development of one or more islet autoantibodies (A), multiple islet autoantibodies (B), and diabetes (C) in children with the DR3/DRB1*04:04-DQ8 or DRB1*04:04-DQ8/DRB1*04:04-DQ8 genotypes. Risks are shown for the GG genotype versus the GA or AA genotypes at rs3763305. P values were calculated using log-rank tests.
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Figure 4
Risk of developing islet autoantibodies and diabetes in FDR children (B, D, and F) and in GP children (A, B, and C) according to genetic susceptibility strata based on HLA DRB1*04 subtype and genetic risk score. Risks are shown for the development of one or more islet autoantibodies (A and B), multiple islet autoantibodies (C and D), and diabetes (E and F). All of the children had the DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype. Genetic susceptibility strata were defined as 1) high-risk DRB1*04 subtype (DR3/DRB1*04:01 or DRB1*04:01-DQ8/DR4 without 04:04 or 04:07) and GRS in the upper quartile (gray), 2) high-risk DRB1*04 subtype and GRS in the second quartile or lower-risk DRB1*04 subtype and GRS in the upper quartile (pink), 3) high-risk DRB1*04 subtype and GRS in the lower 50th centile or lower-risk DRB1*04 subtype and GRS in the second quartile (light blue), and 4) lower-risk DRB1*04 subtype and GRS in the lower 50th centile (green). The strata appear in this order from top to bottom in the risk tables. P values were calculated across all strata using log-rank tests.

Tables

Figures

Table 1

Study characteristics by first-degree relative status

Variable	FDR children (n = 423)	GP children (n = 4,149)
Males	200 (47.3)	2,082 (50.2)
HLA genotype
DR3/4-DQ8	280 (66.2)	2,755 (66.4)
DR4-DQ8/DR4-DQ8	143 (33.8)	1,394 (33.6)
Country
U.S.	194 (45.9)	1,750 (42.2)
Finland	51 (12.1)	792 (19.1)
Germany	92 (21.7)	209 (5.0)
Sweden	86 (20.3)	1,398 (33.7)
First-degree relative with T1D
None	0 (0.0)	4,149 (100.0)
Mother	146 (34.5)	0 (0.0)
Father	180 (42.6)	0 (0.0)
Sibling	79 (18.7)	0 (0.0)
Multiplex	18 (4.3)	0 (0.0)
Outcome events
One or more islet autoantibodies	85 (20.1)	415 (10.0)
Multiple islet autoantibodies	69 (16.3)	255 (6.1)
First-appearing IAA	51 (12.1)	227 (5.5)
First-appearing GADA	46 (10.9)	250 (6.0)
Diabetes	47 (11.1)	145 (3.5)
Genetic risk score available	408 (96.5)	4,006 (96.6)

Data are n (%).

Table 2

Allelic enrichment of DRB1*04 subtypes in FDR children

DR4 subtype	FDR children (alleles, n = 535)	GP children (alleles, n = 5,415)	P^*
DRB104:01*	329 (60.15)	2,788 (51.49)	<0.0001
DRB104:02*	33 (6.03)	291 (5.37)	0.42
DRB104:04*	137 (25.05)	1,928 (35.60)	<0.0001
DRB104:05*	23 (4.20)	226 (4.17)	0.91
DRB104:06*	1 (0.18)	1 (0.02)	0.17
DRB104:07*	7 (1.28)	153 (2.83)	0.035
DRB104:08*	4 (0.73)	25 (0.46)	0.33
DRB104:10*	0 (0.00)	1 (0.02)	1
DRB104:11*	1 (0.18)	1 (0.02)	0.17
DRB104:13*	0 (0.00)	1 (0.02)	1

Data are n (%). Each DRB*04 allele was counted separately (once for children with the DR3/DR4-DQ8 genotype and twice for children with the DR4-DQ8/DR4-DQ8 genotype). DRB*04 subtype information was missing in 77 DR3/DR4-DQ8 and 35 DR4-DQ8/DR4-DQ8 children. Children with the nonrisk DRB1*04:03 allele were excluded a priori from the TEDDY study unless they had a first-degree relative with type 1 diabetes, and the 12 occurrences of this allele in FDR children were therefore not considered.
*P values were calculated using Fisher test.

Table 3

Cox proportional hazards models for developing islet autoantibodies and diabetes in FDR children compared with GP children (reference)

	One or more islet autoantibodies				Multiple islet autoantibodies				Diabetes
	Model 1^*		Model 2^*		Model 1^*		Model 2^*		Model 1^*		Model 2^*
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
FDR child	2.12 (1.65–2.72)	<0.0001	1.82 (1.42–2.35)	<0.0001	2.77 (2.09–3.68)	<0.0001	2.26 (1.70–3.02)	<0.0001	3.69 (2.60–5.23)	<0.0001	2.92 (2.05–4.16)	<0.0001
DRB1^*04:01/x^†			1.42 (1.10–1.83)	0.0075			1.48 (1.08–2.01)	0.014			1.38 (0.93–2.04)	0.1052
Genetic risk score^‡			1.48 (1.34–1.64)	<0.0001			1.66 (1.47–1.88)	<0.0001			1.67 (1.42–1.96)	<0.0001
BTNL2 rs3763305 GG^§			1.05 (0.79–1.40)	0.73			1.39 (0.96–2.00)	0.080			1.80 (1.11–2.93)	0.0175
ITGA1 rs7735139 GG^§			1.18 (0.86–1.63)	0.30			1.06 (0.70–1.60)	0.77			1.11 (0.67–1.87)	0.6776

*Model 1 and 2 are adjusted for sex, country (reference: U.S.), and HLA genotype (reference: DR4-DQ8/DR4-DQ8).
†Reference: DRB1 without 04:01 or 04:01/04:04 and 04:01/04:07.
‡Per unit increase.
§Reference: GA/AA genotype.

Table 4

BTNL2 SNP genotype frequencies in relation to the development of islet autoantibodies and diabetes among TEDDY children with HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 and available genotype information

	Islet autoantibody negative	One or more islet autoantibodies	Multiple islet autoantibodies	Diabetes
HLA DR3/4-DQ8 (n = 3,024), BTNL2 SNP rs3763305
GG	1,839 (69.1)	272 (75.3)	190 (79.8)	120 (82.8)
GA	823 (30.9)	89 (24.7)	48 (20.2)	25 (17.2)
AA	1 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
P^*		0.030	0.0007	0.0007
HLA DR4-DQ8/DR4-DQ8 (n = 1,532), BTNL2 SNP rs3763305
GG	692 (49.7)	89 (64.0)	63 (73.3)	36 (76.6)
GA	571 (41.0)	44 (31.7)	21 (24.4)	10 (21.3)
AA	130 (9.3)	6 (4.3)	2 (2.3)	1 (2.1)
P^*		0.0033	<0.0001	0.0010

Data are n (%).
*Children who remained islet autoantibody negative were compared with children who developed one or more islet autoantibodies, multiple islet autoantibodies, and diabetes using Fisher test.