Failed Genetic Protection: Type 1 Diabetes in the Presence of <i>HLA-DQB1*06:02</i>

Abstract

Certain HLA class II genes increase the risk for type 1 diabetes (T1D) development while others provide protection from disease development. HLA class II alleles encode MHC proteins on antigen-presenting cells, which function to present peptides and activate CD4 T cells. The <i>DRB1*15:01</i> (DR15)-<i>DQA1*01:02</i>-<i>DQB1*06:02</i> (DQ6) haplotype provides dominant protection across all stages of T1D and is a common haplotype found in Caucasians. However, it is present in <1% of people with T1D. Knowing which metabolic, immunologic, and genetic features are unique to individuals who fail genetic protection and develop T1D is important for defining the underlying mechanisms of <i>DQB1*06:02</i>-mediated protection. We describe a T1D cohort with <i>DQB1*06:02</i> (<i>n</i> = 50) and compare them to individuals with T1D and without <i>DQB1*06:02</i> (<i>n</i> = 2,759) who were identified over the last 26 years at the Barbara Davis Center for Diabetes. The age at diagnosis was similar between the cohorts and normally distributed throughout childhood and early adulthood. The average hemoglobin A_1c was 10.8 ± 2.8% (95 ± 7 mmol/mol) at diagnosis in those <i>DQB1*06:02</i> positive. The majority of T1D <i>DQB1*06:02</i> ⁺ individuals were positive for one or more islet autoantibodies; however, there was a greater proportion who were islet autoantibody negative compared with those T1D <i>DQB1*06:02</i> ^- individuals. Interestingly, <i>DQB1*03:02</i>, which confers significant T1D risk, was present in only those <i>DQB1*06:02</i> ⁺ individuals with islet autoantibodies. This is one of the largest studies examining patients presenting with clinical T1D in the presence of <i>DQB1*06:02</i>, which provides a population to study the mechanisms of failed genetic protection against T1D.