HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Abstract

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.

Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes

“…TrialNet studies have also begun to yield other insights into heterogeneity of the disease course. For example, a recent analysis emphasized that HLA type impacts the development of autoantibodies but does not markedly effect progression from that point (25). TrialNet reported differences in the age-and HLA-associated risk of developing additional autoantibodies in single autoantibody-positive relatives who are mIAA positive versus those who are GADA positive, suggesting potentially different disease pathways (23,24).…”

A Global Perspective of Latent Autoimmune Diabetes in Adults

“…However, substantial evidence points towards age-dependent differences in the genetic risk to develop autoimmune diabetes. Specifically, the genetic risk to develop autoimmune diabetes declines with increasing age-at-diagnosis without a clear cut-off but in a graded fashion [60][61][62]. Additionally, LADA was not addressed in the recent cohort study [59] yet a proportion of diabetes cases genetically defined as T1D using a childhoodonset T1D derived GRS did not need insulin at diagnosis.…”

Nucleic acid biomarkers of β cell stress and death in type 1 diabetes

“…A number of immune variables including autoantibody (AAb) positivity, HLA status, and T cell signatures have been used to stratify risk (8–10). In clinical trials, measures of β cell function, such as loss of the early insulin response during intravenous or oral glucose tolerance test (OGTT) or changes in the integrated secretion of C-peptide during an (OGTT) have been utilized to document metabolic decompensation (11).…”