DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis
dc.date.accessioned | 2019-12-13T19:24:00Z | |
dc.date.available | 2019-12-13T19:24:00Z | |
dc.date.created | 2018-08-12T15:06:23Z | |
dc.date.issued | 2018 | |
dc.identifier.citation | Kular, Lara Liu, Yun Ruhrmann, Sabrina Zheleznyakova, Galina Marabita, Francesco Gomez-Cabrero, David James, Tojo Ewing, Ewoud Lindén, Magdalena Górnikiewicz, Bartosz Aeinehband, Shahin Stridh, Pernilla Link, Jenny Andlauer, Till F.M. Gasperi, Christiane Wiendl, Heinz Zipp, Frauke Gold, Ralf Tackenberg, Björn Weber, Frank Hemmer, Bernhard Strauch, Konstantin Heilmann-Heimbach, Stefanie Rawal, Rajesh Schminke, Ulf Schmidt, Carsten O. Kacprowski, Tim Franke, Andre Laudes, Matthias Dilthey, Alexander T. Celius, Elisabeth Gulowsen Søndergaard, Helle Bach Tegnér, Jesper Harbo, Hanne Flinstad Oturai, Annette B. Olafsson, Sigurgeir Eggertsson, Hannes P. Halldorsson, Bjarni V. Hjaltason, Haukur Olafsson, Elias Jonsdottir, Ingileif Stefansson, Kari Olsson, Tomas Piehl, Fredrik Ekström, Tomas J. Kockum, Ingrid Feinberg, Andrew P. Jagodic, Maja . DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis. Nature Communications. 2018, 9(1), 1-15 | |
dc.identifier.uri | http://hdl.handle.net/10852/71620 | |
dc.description.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. | |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis | |
dc.type | Journal article | |
dc.creator.author | Kular, Lara | |
dc.creator.author | Liu, Yun | |
dc.creator.author | Ruhrmann, Sabrina | |
dc.creator.author | Zheleznyakova, Galina | |
dc.creator.author | Marabita, Francesco | |
dc.creator.author | Gomez-Cabrero, David | |
dc.creator.author | James, Tojo | |
dc.creator.author | Ewing, Ewoud | |
dc.creator.author | Lindén, Magdalena | |
dc.creator.author | Górnikiewicz, Bartosz | |
dc.creator.author | Aeinehband, Shahin | |
dc.creator.author | Stridh, Pernilla | |
dc.creator.author | Link, Jenny | |
dc.creator.author | Andlauer, Till F.M. | |
dc.creator.author | Gasperi, Christiane | |
dc.creator.author | Wiendl, Heinz | |
dc.creator.author | Zipp, Frauke | |
dc.creator.author | Gold, Ralf | |
dc.creator.author | Tackenberg, Björn | |
dc.creator.author | Weber, Frank | |
dc.creator.author | Hemmer, Bernhard | |
dc.creator.author | Strauch, Konstantin | |
dc.creator.author | Heilmann-Heimbach, Stefanie | |
dc.creator.author | Rawal, Rajesh | |
dc.creator.author | Schminke, Ulf | |
dc.creator.author | Schmidt, Carsten O. | |
dc.creator.author | Kacprowski, Tim | |
dc.creator.author | Franke, Andre | |
dc.creator.author | Laudes, Matthias | |
dc.creator.author | Dilthey, Alexander T. | |
dc.creator.author | Celius, Elisabeth Gulowsen | |
dc.creator.author | Søndergaard, Helle Bach | |
dc.creator.author | Tegnér, Jesper | |
dc.creator.author | Harbo, Hanne Flinstad | |
dc.creator.author | Oturai, Annette B. | |
dc.creator.author | Olafsson, Sigurgeir | |
dc.creator.author | Eggertsson, Hannes P. | |
dc.creator.author | Halldorsson, Bjarni V. | |
dc.creator.author | Hjaltason, Haukur | |
dc.creator.author | Olafsson, Elias | |
dc.creator.author | Jonsdottir, Ingileif | |
dc.creator.author | Stefansson, Kari | |
dc.creator.author | Olsson, Tomas | |
dc.creator.author | Piehl, Fredrik | |
dc.creator.author | Ekström, Tomas J. | |
dc.creator.author | Kockum, Ingrid | |
dc.creator.author | Feinberg, Andrew P. | |
dc.creator.author | Jagodic, Maja | |
cristin.unitcode | 185,52,11,0 | |
cristin.unitname | Avdeling for helseledelse og helseøkonomi | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1601287 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature Communications&rft.volume=9&rft.spage=1&rft.date=2018 | |
dc.identifier.jtitle | Nature Communications | |
dc.identifier.volume | 9 | |
dc.identifier.doi | https://doi.org/10.1038/s41467-018-04732-5 | |
dc.identifier.urn | URN:NBN:no-74732 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 2041-1723 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/71620/1/41467_2018_Article_4732.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | 2397 |
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