Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Dissect Consortium and The Immunoarray Development Consortium

doi:10.1016/j.ebiom.2023.104804

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Dissect Consortium and The Immunoarray Development Consortium

Research output: Contribution to journal › Article › peer-review

7 Citations (SciVal)

Abstract

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.

Original language	English
Article number	104804
Number of pages	12
Journal	EBioMedicine
Volume	96
Early online date	26 Sept 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104804
Publication status	Published - 31 Oct 2023

Bibliographical note

Funding Information:
The Czech cohort was supported by the Project for conceptual Development of research organization 00023728 from the Ministry of Health in the Czech Republic and by BBMRICZ LM2023033 from the Ministry of Education, Youth, and Sports . This study was also supported in part by The European Union Sixth Framework Programme (project Autocure; lsH-018661), European Science Foundation (ESF) in the framework of the research networking Program European Myositis network (EuMYoNET), the intramural research programs of the National Institute of Environmental Health Sciences (nieHs) and the national institute of arthritis and Musculoskeletal and Skin Diseases (NIAMs), Myositis UK , Arthritis Research UK (now Versus Arthritis) (18474 and 20380), Medical Research Council (MR/N003322/1), National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (NIHR203308).

Funding Information:
VL was funded by the Börje Dahlin Foundation and Fonds de Recherche en Santé du Québec (FRSQ). LMDG was supported by Åke Wibergs stiftelse (M18-0167), Ulla och Gustaf af Uggla stiftelse - KI fond (2018-02670, 2020-02395), Reumatikerförbundet (R-861801, R-932138, R-969653), Konung Gustaf V:s 80-årsfond (FAI-2018-0518, FAI-2019-0597, FAI-2021-0837), Stiftelsen Professor Nanna Svartz Fond (2019-00318, 2020-00377). IEL received support from The Swedish Research Council : 2020-01378, Stockholm Regional Council (ALF), Swedish Heart-Lung foundation, Reumatikerförbundet and ‘Konung Gustaf V:80 year foundation. KLT is a KAW scholar. LR received support from The Swedish Research Council (2018-02399), Reumatikerförbundet (R-939716) and GV:80 (FAI-2020-0658) foundation. MWH was supported by The Swedish Research Council , Torsten Söderberg Foundation , FOREUM, The Swedish Heart-Lung Foundation , Stockholm County Council , Reumatikerförbundet and GV:80 foundation, The Norwegian Research Council . MH received support from The Swedish Research Council , Stockholm Regional Council (ALF), Reumatikerförbundet, Konung Gustaf V:80 year foundation, The Swedish Cancer Association. HC acknowledges support from the Medical Research Council UK (MR/N003322/1) and Myositis UK . The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care .

Keywords

Autoantibody
HLA
Idiopathic inflammatory myopathy
Myositis

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.ebiom.2023.104804Licence: CC BY

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@article{1bbb805c7b0d4e91aae0973eb5075af1,

title = "Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies",

abstract = "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.",

keywords = "Autoantibody, HLA, Idiopathic inflammatory myopathy, Myositis",

author = "{Dissect Consortium and The Immunoarray Development Consortium} and Val{\'e}rie Leclair and Galindo-Feria, {Angeles S} and Simon Rothwell and Olga Kry{\v s}tůfkov{\'a} and Zargar, {Sepehr Sarrafzadeh} and Herman Mann and Diederichsen, {Louise Pyndt} and Helena Andersson and Martin Klein and Sarah Tansley and Lars R{\"o}nnblom and Kerstin Lindblad-Toh and Ann-Christine Syv{\"a}nen and Marie Wahren-Herlenius and Sandling, {Johanna K} and Neil McHugh and Lamb, {Janine A} and Jiri Vencovsk{\'y} and Hector Chinoy and Marie Holmqvist and Matteo Bianchi and Leonid Padyukov and Lundberg, {Ingrid E} and Lina-Marcela Diaz-Gallo",

note = "Funding Information: The Czech cohort was supported by the Project for conceptual Development of research organization 00023728 from the Ministry of Health in the Czech Republic and by BBMRICZ LM2023033 from the Ministry of Education, Youth, and Sports . This study was also supported in part by The European Union Sixth Framework Programme (project Autocure; lsH-018661), European Science Foundation (ESF) in the framework of the research networking Program European Myositis network (EuMYoNET), the intramural research programs of the National Institute of Environmental Health Sciences (nieHs) and the national institute of arthritis and Musculoskeletal and Skin Diseases (NIAMs), Myositis UK , Arthritis Research UK (now Versus Arthritis) (18474 and 20380), Medical Research Council (MR/N003322/1), National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). Funding Information: VL was funded by the B{\"o}rje Dahlin Foundation and Fonds de Recherche en Sant{\'e} du Qu{\'e}bec (FRSQ). LMDG was supported by {\AA}ke Wibergs stiftelse (M18-0167), Ulla och Gustaf af Uggla stiftelse - KI fond (2018-02670, 2020-02395), Reumatikerf{\"o}rbundet (R-861801, R-932138, R-969653), Konung Gustaf V:s 80-{\aa}rsfond (FAI-2018-0518, FAI-2019-0597, FAI-2021-0837), Stiftelsen Professor Nanna Svartz Fond (2019-00318, 2020-00377). IEL received support from The Swedish Research Council : 2020-01378, Stockholm Regional Council (ALF), Swedish Heart-Lung foundation, Reumatikerf{\"o}rbundet and {\textquoteleft}Konung Gustaf V:80 year foundation. KLT is a KAW scholar. LR received support from The Swedish Research Council (2018-02399), Reumatikerf{\"o}rbundet (R-939716) and GV:80 (FAI-2020-0658) foundation. MWH was supported by The Swedish Research Council , Torsten S{\"o}derberg Foundation , FOREUM, The Swedish Heart-Lung Foundation , Stockholm County Council , Reumatikerf{\"o}rbundet and GV:80 foundation, The Norwegian Research Council . MH received support from The Swedish Research Council , Stockholm Regional Council (ALF), Reumatikerf{\"o}rbundet, Konung Gustaf V:80 year foundation, The Swedish Cancer Association. HC acknowledges support from the Medical Research Council UK (MR/N003322/1) and Myositis UK . The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care . ",

year = "2023",

month = oct,

day = "31",

doi = "10.1016/j.ebiom.2023.104804",

language = "English",

volume = "96",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

TY - JOUR

T1 - Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

AU - Dissect Consortium and The Immunoarray Development Consortium

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

N1 - Funding Information: The Czech cohort was supported by the Project for conceptual Development of research organization 00023728 from the Ministry of Health in the Czech Republic and by BBMRICZ LM2023033 from the Ministry of Education, Youth, and Sports . This study was also supported in part by The European Union Sixth Framework Programme (project Autocure; lsH-018661), European Science Foundation (ESF) in the framework of the research networking Program European Myositis network (EuMYoNET), the intramural research programs of the National Institute of Environmental Health Sciences (nieHs) and the national institute of arthritis and Musculoskeletal and Skin Diseases (NIAMs), Myositis UK , Arthritis Research UK (now Versus Arthritis) (18474 and 20380), Medical Research Council (MR/N003322/1), National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). Funding Information: VL was funded by the Börje Dahlin Foundation and Fonds de Recherche en Santé du Québec (FRSQ). LMDG was supported by Åke Wibergs stiftelse (M18-0167), Ulla och Gustaf af Uggla stiftelse - KI fond (2018-02670, 2020-02395), Reumatikerförbundet (R-861801, R-932138, R-969653), Konung Gustaf V:s 80-årsfond (FAI-2018-0518, FAI-2019-0597, FAI-2021-0837), Stiftelsen Professor Nanna Svartz Fond (2019-00318, 2020-00377). IEL received support from The Swedish Research Council : 2020-01378, Stockholm Regional Council (ALF), Swedish Heart-Lung foundation, Reumatikerförbundet and ‘Konung Gustaf V:80 year foundation. KLT is a KAW scholar. LR received support from The Swedish Research Council (2018-02399), Reumatikerförbundet (R-939716) and GV:80 (FAI-2020-0658) foundation. MWH was supported by The Swedish Research Council , Torsten Söderberg Foundation , FOREUM, The Swedish Heart-Lung Foundation , Stockholm County Council , Reumatikerförbundet and GV:80 foundation, The Norwegian Research Council . MH received support from The Swedish Research Council , Stockholm Regional Council (ALF), Reumatikerförbundet, Konung Gustaf V:80 year foundation, The Swedish Cancer Association. HC acknowledges support from the Medical Research Council UK (MR/N003322/1) and Myositis UK . The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care .

PY - 2023/10/31

Y1 - 2023/10/31

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.

KW - Autoantibody

KW - HLA

KW - Idiopathic inflammatory myopathy

KW - Myositis

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DO - 10.1016/j.ebiom.2023.104804

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JO - EBioMedicine

JF - EBioMedicine

M1 - 104804

ER -

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

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Bibliographical note

Keywords

ASJC Scopus subject areas

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