Genetic and Environmental Interactions Modify the Risk of Diabetes-Related Autoimmunity by 6 Years of Age: The TEDDY Study

Abstract

Objective: We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes.

Research design and methods: Infants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years.

Results: Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor.

Conclusions: These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.

Figure 1

Incidence of antibodies among 0- to 6-year-old children in TEDDY by age of seroconversion (incidence and 95% piecewise confidence bands). Autoantibodies appeared in 589 of 8,503 children.

Figure 2

Incidence of IAA only, GADA only, and IA-2A only as first-appearing IA and multiple IA at seroconversion in all participants (A), the general population (B), and FDR of a proband with type 1 diabetes (C). A: IAA only appeared in 252 of 8,503 children, GADA only in 226 of 8,503, and IA-2A only in 9 of 8,503 and multiple IA in 102 of 8,503. B: IAA only appeared in 196 of 7,577 children, GADA only in 183 of 7,577, and IA-2A only in 7 of 7,577 and multiple IA in 79 of 7,577. C: IAA only appeared in 56 of 926 children, GADA only in 43 of 926, and IA-2A only in 2 of 926 and multiple IA in 23 of 926.

Figure 3

Incidence of IAA only, GADA only, and IA-2A only as first-appearing IA and multiple IA at seroconversion by HLA genotype DR3/4 (A), DR4/4 (B), DR4/8 (C), and DR3/3 (D). A: IAA only appeared in 125 of 3,317 children, GADA only in 111 of 3,317, IA-2A only in 3 of 3,317, and multiple IA in 59 of 3,317. B: IAA only appeared in 44 of 1,661 children, GADA only in 34 of 1,661, IA-2A only in 3 of 1,661, and multiple IA in 22 of 1,661. C: IAA only appeared in 53 of 1,470 children, GADA only in 24 of 1,470, IA-2A only in 2 of 1,470, and multiple IA in 9 of 1,470. D: IAA only appeared in 17 of 1,782 children, GADA only in 54 of 1,782, IA-2A only in 1 of 1,782, and multiple IA in 4 of 1,782.

Figure 4

Cumulative incidence of type 1 diabetes among 0- to 6-year-old children in TEDDY by males reporting upper-respiratory infection (URI) before 3 months of age, males not reporting upper-respiratory infection before 3 months of age, females reporting upper-respiratory infection before 3 months of age, and females not reporting upper-respiratory infection before 3 months of age.