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 autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (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 therefore used to determine all DRB alleles in consecutively diagnosed, islet autoantibody positive 1-18 years old type 1 diabetes patients (n=970) and controls (n=448). It was tested whether DRB3, DRB4 or DRB5 alleles were associated 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 with DRB1:04:05:01 it decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with next generation sequencing should prove useful to select participants for prevention or intervention trials.