Abstract

The risk for autoimmunity and subsequently type 1 diabetes is ten-fold higher in children with a first-degree family history of type 1 diabetes (FDR) than in the general population. 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, were identified in FDR children as compared to general population children. After correcting for genetic enrichment, the risks in the FDR and general population children converged but were not identical for multiple islet autoantibodies (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 general population 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.