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The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

Zhao, Lue Ping ; Papadopoulos, George K ; Lybrand, Terry P ; Moustakas, Antonis K ; Bondinas, George P ; Carlsson, Annelie LU orcid ; Larsson, Helena Elding LU ; Ludvigsson, Johnny ; Marcus, Claude and Persson, Martina LU , et al. (2021) In EBioMedicine 69.
Abstract

BACKGROUND: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated.

METHODS: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic... (More)

BACKGROUND: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated.

METHODS: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions.

FINDINGS: Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The "KAG" motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10-64). Three less frequent motifs ("EAV", OR = 2.55, p = 0.025; "RAG", OR = 1.93, p = 0.043; and "RAV", OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs ("REG" and "REV") were equally protective (OR = 0.11, p = 4.23 × 10-4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the "KAG" motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10-14) after adjusting potential confounders.

INTERPRETATIONS: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65.

FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.

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Contribution to journal
publication status
published
subject
keywords
HLA-DRB1 subtypes, Motif analysis, Seroconversion, Structural analysis, Type 1 diabetes
in
EBioMedicine
volume
69
article number
103431
pages
14 pages
publisher
Elsevier
external identifiers
  • scopus:85109099814
  • pmid:34153873
ISSN
2352-3964
DOI
10.1016/j.ebiom.2021.103431
project
Better Diabetes Diagnosis (BDD)
language
English
LU publication?
yes
id
e9f55890-dcec-4840-80a5-08612421fa4a
date added to LUP
2021-06-23 08:50:39
date last changed
2024-04-20 08:49:39
@article{e9f55890-dcec-4840-80a5-08612421fa4a,
  abstract     = {{<p>BACKGROUND: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated.</p><p>METHODS: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions.</p><p>FINDINGS: Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The "KAG" motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10-64). Three less frequent motifs ("EAV", OR = 2.55, p = 0.025; "RAG", OR = 1.93, p = 0.043; and "RAV", OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs ("REG" and "REV") were equally protective (OR = 0.11, p = 4.23 × 10-4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the "KAG" motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10-14) after adjusting potential confounders.</p><p>INTERPRETATIONS: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65.</p><p>FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.</p>}},
  author       = {{Zhao, Lue Ping and Papadopoulos, George K and Lybrand, Terry P and Moustakas, Antonis K and Bondinas, George P and Carlsson, Annelie and Larsson, Helena Elding and Ludvigsson, Johnny and Marcus, Claude and Persson, Martina and Samuelsson, Ulf and Wang, Ruihan and Pyo, Chul-Woo and Nelson, Wyatt C and Geraghty, Daniel E and Rich, Stephen S and Lernmark, Åke}},
  issn         = {{2352-3964}},
  keywords     = {{HLA-DRB1 subtypes; Motif analysis; Seroconversion; Structural analysis; Type 1 diabetes}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2021.103431}},
  doi          = {{10.1016/j.ebiom.2021.103431}},
  volume       = {{69}},
  year         = {{2021}},
}