Háskólinn í ReykjavíkReykjavik UniversityHáskóli ÍslandsUniversity of IcelandKular, LaraLiu, YunRuhrmann, SabrinaZheleznyakova, GalinaMarabita, FrancescoGomez-Cabrero, DavidJames, TojoEwing, EwoudLindén, MagdalenaGórnikiewicz, BartoszAeinehband, ShahinStridh, PernillaLink, JennyAndlauer, Till F. M.Gasperi, ChristianeWiendl, HeinzZipp, FraukeGold, RalfTackenberg, BjörnWeber, FrankHemmer, BernhardStrauch, KonstantinHeilmann-Heimbach, StefanieRawal, RajeshSchminke, UlfSchmidt, Carsten O.Kacprowski, TimFranke, AndreLaudes, MatthiasDilthey, Alexander T.Celius, Elisabeth G.Søndergaard, Helle B.Tegnér, JesperHarbo, Hanne F.Oturai, Annette B.Sigurgeir ÓlafssonEggertsson, HannesHalldórsson, BjarniHjaltason, HaukurElías ÓlafssonJonsdottir, IngileifStefansson, KariOlsson, TomasPiehl, FredrikEkström, Tomas J.Kockum, IngridFeinberg, Andrew P.Jagodic, Maja2019-10-212019-10-212018-06-19Kular, 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/s41467-018-04732-52041-1723 (eISSN)https://hdl.handle.net/20.500.11815/1306These authors contributed equally: Lara Kular, Yun Liu, Ingrid Kockum, Andrew P. Feinberg, Maja Jagodic.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.2397eninfo:eu-repo/semantics/openAccessMultiple sclerosisDNA methylationEpigenomicsMS sjúkdómurDNA kjarnsýraErfðarannsóknirinfo:eu-repo/semantics/articleNature Communications10.1038/s41467-018-04732-5