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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
- Source :
- Kular , L , Liu , Y , Ruhrmann , S , Zheleznyakova , G , Marabita , F , Gomez-Cabrero , D , James , T , Ewing , E , Lindén , M , Górnikiewicz , B , Aeinehband , S , Stridh , P , Link , J , Andlauer , T F M , Gasperi , C , Wiendl , H , Zipp , F , Gold , R , Tackenberg , B , Weber , F , Hemmer , B , Strauch , K , Heilmann-Heimbach , S , Rawal , R , Schminke , U , Schmidt , C O , Kacprowski , T , Franke , A , Laudes , M , Dilthey , A T , Celius , E G , Søndergaard , H B , Tegnér , J , Harbo , H F , Oturai , A B , Olafsson , S , Eggertsson , H P , Halldorsson , B V , Hjaltason , H , Olafsson , E , Jonsdottir , I , Stefansson , K , Olsson , T , Piehl , F , Ekström , T J , Kockum , I , Feinberg , A P & Jagodic , M 2018 , ' DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis ' , Nature Communications , vol. 9 , 2397 , pp. 1-15 .
- Publication Year :
- 2018
-
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.
Details
- Database :
- OAIster
- Journal :
- Kular , L , Liu , Y , Ruhrmann , S , Zheleznyakova , G , Marabita , F , Gomez-Cabrero , D , James , T , Ewing , E , Lindén , M , Górnikiewicz , B , Aeinehband , S , Stridh , P , Link , J , Andlauer , T F M , Gasperi , C , Wiendl , H , Zipp , F , Gold , R , Tackenberg , B , Weber , F , Hemmer , B , Strauch , K , Heilmann-Heimbach , S , Rawal , R , Schminke , U , Schmidt , C O , Kacprowski , T , Franke , A , Laudes , M , Dilthey , A T , Celius , E G , Søndergaard , H B , Tegnér , J , Harbo , H F , Oturai , A B , Olafsson , S , Eggertsson , H P , Halldorsson , B V , Hjaltason , H , Olafsson , E , Jonsdottir , I , Stefansson , K , Olsson , T , Piehl , F , Ekström , T J , Kockum , I , Feinberg , A P & Jagodic , M 2018 , ' DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis ' , Nature Communications , vol. 9 , 2397 , pp. 1-15 .
- Notes :
- English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1322728680
- Document Type :
- Electronic Resource