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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
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    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.

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