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

Lara Kular, Yun Liu, Sabrina Ruhrmann, Galina Zheleznyakova, Francesco Marabita, David Gomez-Cabrero, Tojo James, Ewoud Ewing, Magdalena Lindén, Bartosz Górnikiewicz, Shahin Aeinehband, Pernilla Stridh, Jenny Link, Till F. M. Andlauer, Christiane Gasperi, Heinz Wiendl, Frauke Zipp, Ralf Gold, Björn Tackenberg, Frank Weber, Bernhard Hemmer, Konstantin Strauch, Stefanie Heilmann-Heimbach, Rajesh Rawal, Ulf Schminke, Carsten O. Schmidt, Tim Kacprowski, Andre Franke, Matthias Laudes, Alexander T. Dilthey, Elisabeth G. Celius, Helle B. Søndergaard, Jesper Tegnér, Hanne F. Harbo, Annette B. Oturai, Sigurgeir Olafsson, Hannes P. Eggertsson, Bjarni V. Halldorsson, Haukur Hjaltason, Elias Olafsson, Ingileif Jonsdottir, Kari Stefansson, Tomas Olsson, Fredrik Piehl, Tomas J. Ekström, Ingrid Kockum, Andrew P. Feinberg () and Maja Jagodic ()
Additional contact information
Lara Kular: Center for Molecular Medicine, Karolinska Institutet
Yun Liu: Johns Hopkins University
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
Christiane Gasperi: Technische Universität München
Heinz Wiendl: Klinikum Rechts der Isar, Technische Universität München
Frauke Zipp: Klinikum Rechts der Isar, Technische Universität München
Ralf Gold: Klinikum Rechts der Isar, Technische Universität München
Björn Tackenberg: Klinikum Rechts der Isar, Technische Universität München
Frank Weber: Max Planck Institute of Psychiatry
Bernhard Hemmer: Technische Universität München
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
Elisabeth G. Celius: Oslo University Hospital
Helle B. Søndergaard: Rigshospitalet, University of Copenhagen
Jesper Tegnér: Karolinska Institutet
Hanne F. Harbo: Oslo University Hospital
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
Haukur Hjaltason: The National University of Iceland
Elias Olafsson: The National University of Iceland
Ingileif Jonsdottir: deCODE genetics/Amgen Inc
Kari Stefansson: deCODE genetics/Amgen Inc
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

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-04732-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04732-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-04732-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().