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

Abstract

This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA-DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first-appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086_A [P = 0.03], rs1534422_G [P = 0.006], and rs2327832_G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446_A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.

Figure 1

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

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.

Figure 3

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

Figure 4

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

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).

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).