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

Abstract

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes-associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6-3.02]) and for diabetes (HR 2.92 [95% CI 2.05-4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.

Trial registration: ClinicalTrials.gov NCT00279318.

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.

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.

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.

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.