The a priori genetic susceptibility defines the divergence in risk of developing islet autoimmunity and type 1 diabetes between children from affected and unaffected families

Depending on population, 0.1-1.0% of children will develop autoimmunity to pancreatic beta cells in childhood and subsequently type 1 diabetes (T1D). The risk is increased more than 10x if a child has a family history of T1D. We explored the interaction between genetic susceptibility and this excess risk to understand how other factors may contribute to the increased risk in affected families. Infants were enrolled in TEDDY and monitored for islet autoantibodies and diabetes. Children with high-risk HLA DR3/4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes (n=4572) were selected and risks compared between those who had a first-degree family history of T1D (FDR, n=423) and those from the general population. Additional genetic risk was examined at DR4 subtypes, non-HLA DR and DQ genetic susceptibility as defined by genetic risk scores from 40 susceptibility loci, and through investigation of genotype enrichment of >100,000 SNPs in FDR children. Enriched genetic susceptibility in FDR children was evidenced by increased frequency of the HLA DRB1*04:01-subtype and increased genetic risk scores as compared to general population children (p<0.0001). Additional genotype enrichment was observed for SNPs in the HLA class II region, which were also associated with the development of diabetes (p<0.0001) independently of HLA DR. Stratification of the genetic susceptibility in the children led to complete convergence for the risk of islet autoantibodies and diabetes between the FDR and general population children in the highest risk stratum defined by high genetic risk score and HLA DRB1*0401-subtype and increasing divergence at lower risk strata. Enriched genetic susceptibility in affected families heterogeneously accounts for the increased risk of developing islet autoantibodies and T1D observed in affected families. The findings suggest that additional factors shared within families contribute to a divergence of risk in first-degree relatives with intermediate and low genetic susceptibility.