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

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dc.contributor Háskólinn í Reykjavík
dc.contributor Reykjavik University
dc.contributor Háskóli Íslands
dc.contributor University of Iceland
dc.contributor.author Kular, Lara
dc.contributor.author Liu, Yun
dc.contributor.author Ruhrmann, Sabrina
dc.contributor.author Zheleznyakova, Galina
dc.contributor.author Marabita, Francesco
dc.contributor.author Gomez-Cabrero, David
dc.contributor.author James, Tojo
dc.contributor.author Ewing, Ewoud
dc.contributor.author Lindén, Magdalena
dc.contributor.author Górnikiewicz, Bartosz
dc.contributor.author Aeinehband, Shahin
dc.contributor.author Stridh, Pernilla
dc.contributor.author Link, Jenny
dc.contributor.author Andlauer, Till F. M.
dc.contributor.author Gasperi, Christiane
dc.contributor.author Wiendl, Heinz
dc.contributor.author Zipp, Frauke
dc.contributor.author Gold, Ralf
dc.contributor.author Tackenberg, Björn
dc.contributor.author Weber, Frank
dc.contributor.author Hemmer, Bernhard
dc.contributor.author Strauch, Konstantin
dc.contributor.author Heilmann-Heimbach, Stefanie
dc.contributor.author Rawal, Rajesh
dc.contributor.author Schminke, Ulf
dc.contributor.author Schmidt, Carsten O.
dc.contributor.author Kacprowski, Tim
dc.contributor.author Franke, Andre
dc.contributor.author Laudes, Matthias
dc.contributor.author Dilthey, Alexander T.
dc.contributor.author Celius, Elisabeth G.
dc.contributor.author Søndergaard, Helle B.
dc.contributor.author Tegnér, Jesper
dc.contributor.author Harbo, Hanne F.
dc.contributor.author Oturai, Annette B.
dc.contributor.author Sigurgeir Ólafsson
dc.contributor.author Eggertsson, Hannes
dc.contributor.author Halldórsson, Bjarni
dc.contributor.author Hjaltason, Haukur
dc.contributor.author Elías Ólafsson
dc.contributor.author Jonsdottir, Ingileif
dc.contributor.author Stefansson, Kari
dc.contributor.author Olsson, Tomas
dc.contributor.author Piehl, Fredrik
dc.contributor.author Ekström, Tomas J.
dc.contributor.author Kockum, Ingrid
dc.contributor.author Feinberg, Andrew P.
dc.contributor.author Jagodic, Maja
dc.date.accessioned 2019-10-21T16:06:30Z
dc.date.available 2019-10-21T16:06:30Z
dc.date.issued 2018-06-19
dc.identifier.citation Kular, L., Liu, Y., Ruhrmann, S., Zheleznyakova, G., Marabita, F., Gomez-Cabrero, D., … Jagodic, M. (2018). DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications, 9(1), 2397. https://doi.org/10.1038/s41467-018-04732-5
dc.identifier.issn 2041-1723 (eISSN)
dc.identifier.uri https://hdl.handle.net/20.500.11815/1306
dc.description These authors contributed equally: Lara Kular, Yun Liu, Ingrid Kockum, Andrew P. Feinberg, Maja Jagodic.
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.description.sponsorship This work was supported by grants from the Swedish Research Council, the Swedish Association for Persons with Neurological Disabilities, the Swedish Brain Foundation, the Swedish MS Foundation, Petrus and Augusta Hedlunds Foundation, the Swedish AFA Insurance, Knut and Alice Wallenberg Foundation, the Stockholm County Council (ALF project), and AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration). A.P.F. received grant support from NIH (DP1 ES022579). L.K. was supported by fellowship from the Margaretha af Ugglas Foundation. D.G.-C. and J.T. were supported by EU FP7 306000 STATegra. Y.L. was supported in part by the National Natural Science Foundation (grant no. 31471212). We acknowledge the International Multiple Sclerosis Genetics Consortium (IMSGC) for providing SNP genotypes used in this study and BEA core facility (Karolinska Institutet) for processing 450K array data on monocytes. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX). The Norwegian MS Registry and Biobank and the MS research group in Oslo are acknowledged for access to data from Norwegian MS patients. B.H. was supported by the German research foundation in the framework of the Collaborative research group TR128, the German MS competence network, and the EU project MultipleMS. This work was supported by the German Ministry for Education and Research (BMBF) as part of the “German Competence Network Multiple Sclerosis” (KKNMS) (grant nos. 01GI0916 and 01GI0917). F.Z., H.W., and R.G. were supported by the German research foundation in the framework of the Collaborative research group TR128, the German MS competence network. The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The collection of probands in the Heinz Nixdorf RECALL Study (HNR) (PIs: K.-H. Jöckel, R. Erbel) was supported by the Heinz Nixdorf Foundation. The genotyping of HNR probands was financed through a grant of the BMBF to M. M. Nöthen. The Dortmund Health Study was supported by the German Migraine and Headache Society (DMKG) and unrestricted grants of equal share from Almirall, AstraZeneca, Berlin-Chemie, Boehringer, Boots Healthcare, GlaxoSmithKline (GSK), Janssen-Cilag, McNeil Pharma, Merck Sharp & Dohme (MSD), and Pfizer to the University of Münster. Blood collection was done through funds from the Institute of Epidemiology and Social Medicine, University of Münster (K. Berger and J. Wellmann), genotyping was supported by the BMBF (grant no. 01ER0816). SHIP is part of the Community Medicine Research Network of the University Medicine Greifswald, Germany (www.community-medicine.de), which was initiated and funded by the BMBF (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; genome-wide data have been supported by the BMBF (grant no. 03ZIK012). The FoCus study was supported by the BMBF (grant no. 0315540A).
dc.format.extent 2397
dc.language.iso en
dc.publisher Springer Science and Business Media LLC
dc.relation.ispartofseries Nature Communications;9(1)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Multiple sclerosis
dc.subject DNA methylation
dc.subject Epigenomics
dc.subject MS sjúkdómur
dc.subject DNA kjarnsýra
dc.subject Erfðarannsóknir
dc.title DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
dc.type info:eu-repo/semantics/article
dcterms.license This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.description.version Peer reviewed
dc.identifier.journal Nature Communications
dc.identifier.doi 10.1038/s41467-018-04732-5
dc.contributor.department Læknadeild (HÍ)
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.school Tækni- og verkfræðideild (HR)
dc.contributor.school School of Science and Engineering (RU)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)

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