Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1
(2022) In Diabetes Care 45(7). p.1610-1620- Abstract
OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to 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 HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.
RESULTS: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P... (More)
OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to 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 HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.
RESULTS: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10-4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10-3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10-3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.
CONCLUSIONS: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex.
(Less)
- author
- Zhao, Lue Ping
; Skyler, Jay
; Papadopoulos, George K
; Pugliese, Alberto
; Najera, James Antonio
; Bondinas, George P
; Moustakas, Antonis K
; Wang, Ruihan
; Pyo, Chul-Woo
; Nelson, Wyatt C
; Geraghty, Daniel E
and Lernmark, Åke
LU
(Less) - organization
- publishing date
- 2022-05-27
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Diabetes Care
- volume
- 45
- issue
- 7
- pages
- 1610 - 1620
- publisher
- American Diabetes Association
- external identifiers
-
- scopus:85134361445
- pmid:35621697
- ISSN
- 1935-5548
- DOI
- 10.2337/dc21-1628
- project
- Etiology of autoimmune (type 1) diabetes
- language
- English
- LU publication?
- yes
- id
- a51a16e9-cabf-412a-992c-0423cc155ded
- date added to LUP
- 2022-06-01 09:31:48
- date last changed
- 2025-01-24 17:05:48
@article{a51a16e9-cabf-412a-992c-0423cc155ded,
abstract = {{<p>OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).</p><p>RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset.</p><p>RESULTS: The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 ∗ 10-3) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18β in the signal peptide and β57 in the β-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 ∗ 10-4) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 ∗ 10-3). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAAs) (P = 3.34 ∗ 10-3), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c levels throughout the follow-up.</p><p>CONCLUSIONS: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18β within the signal peptide may be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex.</p>}},
author = {{Zhao, Lue Ping and Skyler, Jay and Papadopoulos, George K and Pugliese, Alberto and Najera, James Antonio and Bondinas, George P and Moustakas, Antonis K and Wang, Ruihan and Pyo, Chul-Woo and Nelson, Wyatt C and Geraghty, Daniel E and Lernmark, Åke}},
issn = {{1935-5548}},
language = {{eng}},
month = {{05}},
number = {{7}},
pages = {{1610--1620}},
publisher = {{American Diabetes Association}},
series = {{Diabetes Care}},
title = {{Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1}},
url = {{http://dx.doi.org/10.2337/dc21-1628}},
doi = {{10.2337/dc21-1628}},
volume = {{45}},
year = {{2022}},
}