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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)

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posted on 2024-03-18, 16:08 authored by Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Alberto Pugliese, Hemang M. Parikh, Bill Kwok, Terry P. Lybrand, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark

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 (DPT-1) and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet (TN07). 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 1) The current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (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). 2) 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). 3) 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). 4) 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.

Funding

The study was supported by a grant (R01 DK132406) from National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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