TY - JOUR
T1 - Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
AU - Leclair, Valérie
AU - Galindo-Feria, Angeles S
AU - Rothwell, Simon
AU - Kryštůfková, Olga
AU - Zargar, Sepehr Sarrafzadeh
AU - Mann, Herman
AU - Diederichsen, Louise Pyndt
AU - Andersson, Helena
AU - Klein, Martin
AU - Tansley, Sarah
AU - Rönnblom, Lars
AU - Lindblad-Toh, Kerstin
AU - Syvänen, Ann-Christine
AU - Wahren-Herlenius, Marie
AU - Sandling, Johanna K
AU - McHugh, Neil
AU - Lamb, Janine A
AU - Vencovský, Jiri
AU - Chinoy, Hector
AU - Holmqvist, Marie
AU - Bianchi, Matteo
AU - Padyukov, Leonid
AU - Lundberg, Ingrid E
AU - Diaz-Gallo, Lina-Marcela
AU - Dissect Consortium and The Immunoarray Development Consortium
N1 - Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2023/10
Y1 - 2023/10
N2 - BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM.METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules.FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup.INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features.FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
AB - BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM.METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules.FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup.INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features.FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
UR - http://www.scopus.com/inward/record.url?scp=85173024531&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104804
DO - 10.1016/j.ebiom.2023.104804
M3 - Journal article
C2 - 37769433
SN - 2352-3964
VL - 96
JO - EBioMedicine
JF - EBioMedicine
M1 - 104804
ER -