IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-04732-5.html
   My bibliography  Save this article

DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis

Author

Listed:
  • Lara Kular

    (Center for Molecular Medicine, Karolinska Institutet)

  • Yun Liu

    (Johns Hopkins University
    Fudan University Shanghai Medical College)

  • Sabrina Ruhrmann

    (Center for Molecular Medicine, Karolinska Institutet)

  • Galina Zheleznyakova

    (Center for Molecular Medicine, Karolinska Institutet)

  • Francesco Marabita

    (Center for Molecular Medicine, Karolinska Institutet)

  • David Gomez-Cabrero

    (Karolinska Institutet)

  • Tojo James

    (Center for Molecular Medicine, Karolinska Institutet)

  • Ewoud Ewing

    (Center for Molecular Medicine, Karolinska Institutet)

  • Magdalena Lindén

    (Center for Molecular Medicine, Karolinska Institutet)

  • Bartosz Górnikiewicz

    (Center for Molecular Medicine, Karolinska Institutet)

  • Shahin Aeinehband

    (Center for Molecular Medicine, Karolinska Institutet)

  • Pernilla Stridh

    (Center for Molecular Medicine, Karolinska Institutet)

  • Jenny Link

    (Center for Molecular Medicine, Karolinska Institutet)

  • Till F. M. Andlauer

    (Max Planck Institute of Psychiatry
    Technische Universität München
    Klinikum Rechts der Isar, Technische Universität München)

  • Christiane Gasperi

    (Technische Universität München
    Klinikum Rechts der Isar, Technische Universität München)

  • Heinz Wiendl

    (Klinikum Rechts der Isar, Technische Universität München
    University of Münster)

  • Frauke Zipp

    (Klinikum Rechts der Isar, Technische Universität München
    University Medicine Mainz, Johannes Gutenberg University Mainz)

  • Ralf Gold

    (Klinikum Rechts der Isar, Technische Universität München
    Ruhr-University Bochum)

  • Björn Tackenberg

    (Klinikum Rechts der Isar, Technische Universität München
    Marburg University)

  • Frank Weber

    (Max Planck Institute of Psychiatry
    Klinikum Rechts der Isar, Technische Universität München)

  • Bernhard Hemmer

    (Technische Universität München
    Klinikum Rechts der Isar, Technische Universität München
    Munich Cluster for Systems Neurology (SyNergy))

  • Konstantin Strauch

    (Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität)

  • Stefanie Heilmann-Heimbach

    (University of Bonn School of Medicine)

  • Rajesh Rawal

    (University of Münster)

  • Ulf Schminke

    (University Medicine Greifswald)

  • Carsten O. Schmidt

    (University Medicine Greifswald)

  • Tim Kacprowski

    (Ernst Moritz Arndt University and University Medicine Greifswald)

  • Andre Franke

    (Kiel University)

  • Matthias Laudes

    (Kiel University)

  • Alexander T. Dilthey

    (University of Oxford
    Institute of Medical Microbiology and Hospital Hygiene Heinrich-Heine-University Düsseldorf)

  • Elisabeth G. Celius

    (Oslo University Hospital
    University of Oslo)

  • Helle B. Søndergaard

    (Rigshospitalet, University of Copenhagen)

  • Jesper Tegnér

    (Karolinska Institutet
    King Abdullah University of Science and Technology)

  • Hanne F. Harbo

    (Oslo University Hospital
    University of Oslo)

  • Annette B. Oturai

    (Rigshospitalet, University of Copenhagen)

  • Sigurgeir Olafsson

    (deCODE genetics/Amgen Inc)

  • Hannes P. Eggertsson

    (deCODE genetics/Amgen Inc)

  • Bjarni V. Halldorsson

    (deCODE genetics/Amgen Inc
    Reykjavik University)

  • Haukur Hjaltason

    (The National University of Iceland
    University of Iceland)

  • Elias Olafsson

    (The National University of Iceland
    University of Iceland)

  • Ingileif Jonsdottir

    (deCODE genetics/Amgen Inc
    University of Iceland
    The National University Hospital of Iceland)

  • Kari Stefansson

    (deCODE genetics/Amgen Inc
    University of Iceland)

  • Tomas Olsson

    (Center for Molecular Medicine, Karolinska Institutet)

  • Fredrik Piehl

    (Center for Molecular Medicine, Karolinska Institutet)

  • Tomas J. Ekström

    (Center for Molecular Medicine, Karolinska Institutet)

  • Ingrid Kockum

    (Center for Molecular Medicine, Karolinska Institutet)

  • Andrew P. Feinberg

    (Johns Hopkins University)

  • Maja Jagodic

    (Center for Molecular Medicine, Karolinska Institutet)

Abstract

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p

Suggested Citation

  • Lara Kular & Yun Liu & Sabrina Ruhrmann & Galina Zheleznyakova & Francesco Marabita & David Gomez-Cabrero & Tojo James & Ewoud Ewing & Magdalena Lindén & Bartosz Górnikiewicz & Shahin Aeinehband & Per, 2018. "DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04732-5
    DOI: 10.1038/s41467-018-04732-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-04732-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-04732-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Tina Roostaei & Hans-Ulrich Klein & Yiyi Ma & Daniel Felsky & Pia Kivisäkk & Sarah M. Connor & Alexandra Kroshilina & Christina Yung & Belinda J. Kaskow & Xiaorong Shao & Brooke Rhead & José M. Ordová, 2021. "Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Matthias Wielscher & Pooja R. Mandaviya & Brigitte Kuehnel & Roby Joehanes & Rima Mustafa & Oliver Robinson & Yan Zhang & Barbara Bodinier & Esther Walton & Pashupati P. Mishra & Pascal Schlosser & Ro, 2022. "DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04732-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.