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

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

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 < 3.32 × 10-8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

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Authors (48)

  • Photo of  Lara Kular

    Lara Kular

  • Photo of  Yun Liu

    Yun Liu

  • Photo of  Sabrina Ruhrmann

    Sabrina Ruhrmann

  • Photo of  Galina Zheleznyakova

    Galina Zheleznyakova

  • Photo of  Francesco Marabita

    Francesco Marabita

  • Photo of  David Gomez-Cabrero

    David Gomez-Cabrero

  • Photo of  Tojo James

    Tojo James

  • Photo of  Ewoud Ewing

    Ewoud Ewing

  • Photo of  Magdalena Lindén

    Magdalena Lindén

  • Photo of  Shahin Aeinehband

    Shahin Aeinehband

  • Photo of  Pernilla Stridh

    Pernilla Stridh

  • Photo of  Jenny Link

    Jenny Link

  • Photo of  Till Andlauer

    Till Andlauer

  • Photo of  Christiane Gasperi

    Christiane Gasperi

  • Photo of  Heinz Wiendl

    Heinz Wiendl

  • Photo of  Frauke Zipp

    Frauke Zipp

  • Photo of  Ralf Gold

    Ralf Gold

  • Photo of  Björn Tackenberg

    Björn Tackenberg

  • Photo of  Frank Weber

    Frank Weber

  • Photo of  Bernhard Hemmer

    Bernhard Hemmer

  • Photo of  Konstantin Strauch

    Konstantin Strauch

  • Photo of  Stefanie Heilmann-Heimbach

    Stefanie Heilmann-Heimbach

  • Photo of  Rajesh Rawal

    Rajesh Rawal

  • Photo of  Ulf Schminke

    Ulf Schminke

  • Photo of  Carsten Schmidt

    Carsten Schmidt

  • Photo of  Tim Kacprowski

    Tim Kacprowski

  • Photo of  Andre Franke

    Andre Franke

  • Photo of  Matthias Laudes

    Matthias Laudes

  • Photo of  Alexander Dilthey

    Alexander Dilthey

  • Photo of  Elisabeth Celius

    Elisabeth Celius

  • Photo of  Helle Søndergaard

    Helle Søndergaard

  • Photo of  Jesper Tegnér

    Jesper Tegnér

  • Photo of  Hanne Harbo

    Hanne Harbo

  • Photo of  Annette Oturai

    Annette Oturai

  • Photo of  Sigurgeir Olafsson

    Sigurgeir Olafsson

  • Photo of  Hannes Eggertsson

    Hannes Eggertsson

  • Photo of  Bjarni Halldorsson

    Bjarni Halldorsson

  • Photo of  Haukur Hjaltason

    Haukur Hjaltason

  • Photo of  Elias Olafsson

    Elias Olafsson

  • Photo of  Ingileif Jonsdottir

    Ingileif Jonsdottir

  • Photo of  Kari Stefansson

    Kari Stefansson

  • Photo of  Tomas Olsson

    Tomas Olsson

  • Photo of  Fredrik Piehl

    Fredrik Piehl

  • Photo of  Tomas Ekström

    Tomas Ekström

  • Photo of  Ingrid Kockum

    Ingrid Kockum

  • Photo of  Andrew Feinberg

    Andrew Feinberg

  • Photo of  Maja Jagodic

    Maja Jagodic

Keywords

Details

Category:
Articles
Type:
artykuły w czasopismach
Published in:
Nature Communications no. 9, pages 1 - 15,
ISSN: 2041-1723
Language:
English
Publication year:
2018
Bibliographic description:
Kular L., Liu Y., Ruhrmann S., Zheleznyakova G., Marabita F., Gomez-Cabrero D., James T., Ewing E., Lindén M., Górnikiewicz B., Aeinehband S., Stridh P., Link J., Andlauer T., Gasperi C., Wiendl H., Zipp F., Gold R., Tackenberg B., Weber F., Hemmer B., Strauch K., Heilmann-Heimbach S., Rawal R., Schminke U., Schmidt C., Kacprowski T., Franke A., Laudes M., Dilthey A., Celius E., Søndergaard H., Tegnér J., Harbo H., Oturai A., Olafsson S., Eggertsson H., Halldorsson B., Hjaltason H., Olafsson E., Jonsdottir I., Stefansson K., Olsson T., Piehl F., Ekström T., Kockum I., Feinberg A., Jagodic M.: DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis// Nature Communications -Vol. 9,iss. 1 (2018), s.1-15
DOI:
Digital Object Identifier (open in new tab) 10.1038/s41467-018-04732-5
Verified by:
Gdańsk University of Technology

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