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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)
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Lara Kular
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Yun Liu
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Sabrina Ruhrmann
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Galina Zheleznyakova
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Francesco Marabita
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David Gomez-Cabrero
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Tojo James
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Ewoud Ewing
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Magdalena Lindén
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Shahin Aeinehband
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Pernilla Stridh
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Jenny Link
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Till Andlauer
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Christiane Gasperi
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Heinz Wiendl
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Frauke Zipp
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Ralf Gold
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Björn Tackenberg
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Frank Weber
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Bernhard Hemmer
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Konstantin Strauch
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Stefanie Heilmann-Heimbach
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Rajesh Rawal
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Ulf Schminke
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Carsten Schmidt
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Tim Kacprowski
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Andre Franke
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Matthias Laudes
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Alexander Dilthey
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Elisabeth Celius
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Helle Søndergaard
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Jesper Tegnér
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Hanne Harbo
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Annette Oturai
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Sigurgeir Olafsson
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Hannes Eggertsson
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Bjarni Halldorsson
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Haukur Hjaltason
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Elias Olafsson
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Ingileif Jonsdottir
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Kari Stefansson
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Tomas Olsson
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Fredrik Piehl
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Tomas Ekström
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Ingrid Kockum
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Andrew Feinberg
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Maja Jagodic
Cite as
Full text
- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1038/s41467-018-04732-5
- License
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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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