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Kular, Lara; Liu, Yun; Ruhrmann, Sabrina; Zheleznyakova, Galina; Marabita, Francesco; Gomez-Cabrero, David; James, Tojo; Ewing, Ewoud; Linden, Magdalena; Gornikiewicz, 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 G.; Sondergaard, Helle B.; Tegner, Jesper; Harbo, Hanne F.; Oturai, Annette B.; Olafsson, Sigurgeir; Eggertsson, Hannes P.; Halldorsson, Bjarni V.; Hjaltason, Haukur; Olafsson, Elias; Jonsdottir, Ingileif; Stefansson, Kari; Olsson, Tomas; Piehl, Fredrik; Ekstroem, Tomas J.; Kockum, Ingrid; Feinberg, Andrew P.; Jagodic, Maja (2018): DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis. In: Nature Communications, Vol. 9, 2397
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Abstract

The human leukocyte antigen (HLA) haplotype DRB1(star)15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1(star)15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1(star)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(star)15:01 and also identifies a protective variant (rs9267649, p < 3.32 x 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(star)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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