Role of Type 1 Diabetes-Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study

Abstract

The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying high-risk HLA genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]), and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.

Figure 1

Children were enrolled from the GP in the TEDDY study based on their high-risk HLA genotypes, and SNPs were analyzed using the ImmunoChip (n = 5,164). The figure illustrates a summary of the 41 SNPs replicated from the study by Barrett et al. (4). SNPs associated with nominally significant increased risk for autoantibody positivity are indicated by upward diagonal lines, and SNPs associated with protection from autoantibody positivity are indicated by horizontal lines. The upper 95% CI is indicated by the upper bar of the box, the lower 95% CI is indicated by the lower bar of the box, and the HR is indicated by a solid bar in the middle of the box. HRs were different from 1.0, but only rs3184504 in SH2B3 (P = 0.00015) among the DR4/4 or DR4/8 carriers were significant after Bonferroni correction. A: HRs and 95% CIs in 40 autoantibody-positive subjects and 1,121 autoantibody-negative subjects carrying the DRB1*03-DQA1*05-DQB1*02:01/DRB1*03-DQA1*05-DQB1*02:01 (DR3/3) HLA genotype (n = 1,161). B: HRs and 95% CIs in 188 autoantibody-positive subjects and 1,893 autoantibody-negative subjects carrying the DRB1*04-DQA1*03-DQB1*03:02/DRB1*03-DQA1*05-DQB1*02:01 (DR3/4) HLA genotype (n = 2,081). C: HRs and 95% CIs in 122 autoantibody-positive subjects and 1,800 autoantibody-negative subjects carrying either DRB1*04-DQA1*03-DQB1*03:02/DRB1*04-DQA1*03-DQB1*03:02 (DR4/4) or DRB1*04-DQA1*03-DQB1*03:02/DRB1*08-DQA1*04-DQB1*04:02 (DR4/8) HLA genotypes (n = 1,922). ***, indicates significance after Bonferroni correction.