HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population

Abstract

Objective: A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as >85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403.

Research design and methods: We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequence-specific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes.

Results: By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is approximately 55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P = 0.02) with either protective allele, and the risk is 20 vs. 2% (P = 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies.

Conclusions: The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.