Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes

The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1–18 years with islet autoantibody–positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10(−36)), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.