Human leucocyte antigen (HLA) class II genes confer significant genetic risk for type 1 diabetes (T1D) development and protection. The dominant protection afforded by the DRB1*15:01 (DR15)-DQA1*01:02-DQB1*06:02 (DQ6) haplotype across all stages of T1D is well documented. This is a common haplotype found in Caucasians but 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 a T1D cohort lacking DQB1*06:02 (n=2,759), which were both identified over the last 26 years at the Barbara Davis Center, a large tertiary referral center in the Rocky Mountain Region. As expected, the average A1C was 10.8 ± 2.8% at diagnosis in 0602+ individuals. The age at diagnosis was similar between the 0602+ and 0602- participants (10.8 ± 6.0 vs. 12.5 ± 8.7 years, respectively, p=0.069) and normally distributed throughout childhood and early adulthood. The majority of 0602+ individuals with T1D were positive for one or more islet autoantibodies; however, there was a greater proportion that were islet autoantibody negative compared to 0602- individuals with T1D (p=0.004). The presence of autoantibodies directed against insulinoma antigen-2 (IA-2) was less common in 0602+ individuals (p=0.005), while the percentage of antibodies directed against GAD65, insulin and zinc transporter 8 were similar between 0602+ and 0602- individuals. Interestingly, the DQ allele on the other chromosome, DQB1*03:02 (DQ8) which confers significant T1D risk, was present in 0602+ individuals with islet autoantibodies and not in individuals without autoantibodies (p=0.002).
In conclusion, studying the clinical, immunologic and genetic features of individuals that failed genetic protection holds promise for understanding mechanisms that ultimately lead to beta cell destruction in T1D.
K. Simmons: None. A.M. Mitchell: None. A. Alkanani: None. K. McDaniel: None. E. Baschal: None. T. Armstrong: None. L. Pyle: None. L. Yu: None. A.W. Michels: Other Relationship; Self; ImmunoMolecular Therapeutics, LLC.
National Institutes of Health (DK095995, DK108868, DK110845, DK032083, K12DK094712-08); JDRF/Children’s Diabetes Foundation (2-SRA-2016-202-5-B); Colorado Clinical and Translational Science Institute (TR001082)