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Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis
  1. Lourdes Ortiz-Fernández1,
  2. Francisco David Carmona2,
  3. Raquel López-Mejías3,
  4. Maria Francisca González-Escribano4,
  5. Paul A Lyons5,
  6. Ann W Morgan6,
  7. Amr H Sawalha7,
  8. Kenneth G C Smith5,
  9. Miguel A González-Gay3,8,
  10. Javier Martín1
  11. Spanish GCA Study Group, UK GCA Consortium, Turkish Takayasu Study Group, Vasculitis Clinical Research Consortium, IgAV Study Group, AAV Study group.
    1. 1Instituto de Parasitologia y Biomedicina Lopez-Neyra, Granada, Spain
    2. 2Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada, Spain
    3. 3Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
    4. 4Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS,CSIC, US), Sevilla, Spain
    5. 5Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK
    6. 6Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
    7. 7Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
    8. 8School of Medicine, University of Cantabria, Santander, Spain
    1. Correspondence to Lourdes Ortiz-Fernández, Instituto de Parasitología y Biomedicina LópezNeyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud. Avenida del Conocimiento, 17 18016-Armilla, Granada, Spain; lourdes{at}ipb.csic.es

    Abstract

    Objetive Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis.

    Methods Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu’s arteritis , antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data.

    Results The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression.

    Conclusions Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.

    • systemic sclerosis
    • autoantibodies
    • outcomes research

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors LO-F, FDC and JM were involved in the conception and design of the study as well as to the interpretation of data. LO-F performed the statistical analyses and drafted the manuscript. FDC and JM critically revised the manuscript for important intellectual content. RLM, PL, AWM, AS, KS, MAG-G and the consortium members were involved in the acquisition of data. All authors revised and approved the final version of the manuscript.

    • Funding This work was supported by the following grants: P12-BIO-1395 fromConsejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) and the Cooperative Research Thematic Network (RETICS) programme, RD16/0012/0004 (RIER), from Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain), and the National Institute Of Arthritis And Musculoskeletal And Skin Diseases of the National Institutes of Health under Award Number R01AR070148. FDC was recipient of a grant from the ’Ramón y Cajal’ programme of the Spanish Ministry of Economy and Competitiveness (RYC-2014–16458). RLM is supported by the Miguel Servet I programme of the Spanish Ministry of Economy and Competitiveness through the grant CP16/00033. The UKGCA Consortium was funded by Research into Ageing and The Wellcome Trust and is currently supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, NIHR Leeds Diagnostic Evidence Co-operative, Medical Research Council and the Ann Wilks Memorial Fund. This article presents independent research funded in part by the NIHR

    • Disclaimer The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the Department of Health.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Comité de Bioética del Consejo Superior de Investigaciones Científicas and the local ethical committees of the different participating centres.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The Collaborators details are included in online supplementary material "Supplementary_Note_R1".

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