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- Title
HLA Class II (DR , DQ, DP) Genes Were Separately Associated With the Progression From Seroconversion to Onset of Type 1 Diabetes Among Participants in Two Diabetes Prevention Trials (DPT-1 and TN07).
- Authors
Zhao, Lue Ping; Papadopoulos, George K.; Skyler, Jay S.; Pugliese, Alberto; Parikh, Hemang M.; Kwok, William W.; Lybrand, Terry P.; Bondinas, George P.; Moustakas, Antonis K.; Wang, Ruihan; Pyo, Chul-Woo; Nelson, Wyatt C.; Geraghty, Daniel E.; Lernmark, Åke
- Abstract
OBJECTIVE: To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1 , DQB1 , DRB1 , DRB3 , DRB4 , DRB5 , DPA1 , DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression. RESULTS: First, the current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10−3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10−3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). Second, after adjusting for DQ , DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10−3, respectively). Third, DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02 , sharing the DRB1*03:01 , had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). Fourth, through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression. CONCLUSIONS: These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.
- Subjects
TYPE 1 diabetes; HIV seroconversion; AUTOIMMUNE diseases; SEROCONVERSION; DIABETES; GENES; LINKAGE disequilibrium
- Publication
Diabetes Care, 2024, Vol 47, Issue 5, p826
- ISSN
0149-5992
- Publication type
Article
- DOI
10.2337/dc23-1947