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

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

Nature communications, 2018-12 [Periódico revisado por pares]

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Título:
DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis
Autor: 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
É parte de: Nature communications, 2018-12
Descrição: 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.
Idioma: Norueguês

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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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