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

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 DRB1*15:01 (DR15)-DQA1*01:02-DQB1*06:02 (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 DQB1*06:02-mediated protection. We describe a T1D cohort with DQB1*06:02 (n = 50) and compare them to individuals with T1D and without DQB1*06:02 (n = 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 DQB1*06:02 positive. The majority of T1D DQB1*06:02 ⁺ individuals were positive for one or more islet autoantibodies; however, there was a greater proportion who were islet autoantibody negative compared with those T1D DQB1*06:02 ^- individuals. Interestingly, DQB1*03:02, which confers significant T1D risk, was present in only those DQB1*06:02 ⁺ individuals with islet autoantibodies. This is one of the largest studies examining patients presenting with clinical T1D in the presence of DQB1*06:02, which provides a population to study the mechanisms of failed genetic protection against T1D.

Figure 1

A: Distribution of age at diagnosis with T1D in DQB1*06:02⁺ participants (n = 50). B: Age at diagnosis of T1D DQB1*06:02⁺ participants that had islet autoantibodies measured (n = 49). Mean age of autoantibody-negative (Ab⁻) participants was 8.5 ± 5.0 years (n = 16), and mean age of autoantibody-positive (Ab⁺) participants was 11.8 ± 6.2 years (n = 33); P = 0.069.

Figure 2

A–D: Islet autoantibody levels in DQB1*06:02⁺ and DQB1*06:02⁻ T1D individuals for IAA (A), IA-2A (B), GADA (C), and ZnT8A (D). P = 0.006 for IAA, P < 0.001 for IA-2A, P = 0.20 for GADA, and P = 0.76 for ZnT8A. IAA values were included if measured within 21 days of T1D diagnosis. The dotted line is at the cutoff for each autoantibody positivity.

Figure 3

HLA alleles in DQB1*06:02⁺ and DQB1*06:02⁻ T1D individuals compared by islet autoantibody positive (Ab⁺) versus autoantibody negative (Ab⁻) status. n = 33 for 0602⁺ Ab⁺, n = 16 for 0602⁺ Ab⁻, n = 2,077 for 0602⁻ Ab⁺, and n = 670 for 0602⁻ Ab⁻.