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

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden. Department of Pediatrics, Lund University, Lund, Sweden. Department of Pediatrics, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Department of Clinical Neurosciences, Karolinska Institutet, Solna, Sweden. Department of Clinical Science, Karolinska Institutet, Huddinge, Sweden. Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden ake.lernmark@med.lu.se.

Diabetes. 2016;(3):710-8
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Abstract

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.