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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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
  • Beteiligte: 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; [...]
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-018-04732-5
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The human leukocyte antigen (HLA) haplotype <jats:italic>DRB1*15</jats:italic>:<jats:italic>01</jats:italic> is the major risk factor for multiple sclerosis (MS). Here, we find that <jats:italic>DRB1*15</jats:italic>:<jats:italic>01</jats:italic> is hypomethylated and predominantly expressed in monocytes among carriers of <jats:italic>DRB1*15</jats:italic>:<jats:italic>01</jats:italic>. A differentially methylated region (DMR) encompassing <jats:italic>HLA-DRB1</jats:italic> exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that <jats:italic>HLA</jats:italic> variants mediate risk for MS via changes in the <jats:italic>HLA-DRB1</jats:italic> DMR that modify <jats:italic>HLA-DRB1</jats:italic> expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from <jats:italic>DRB1*15</jats:italic>:<jats:italic>01</jats:italic> and also identifies a protective variant (rs9267649, <jats:italic>p</jats:italic> &lt; 3.32 × 10<jats:sup>−8</jats:sup>, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the <jats:italic>HLA-DRB1</jats:italic> DMR and reduced expression of <jats:italic>HLA-DRB1</jats:italic>, suggesting a modulation of the <jats:italic>DRB1*15</jats:italic>:<jats:italic>01</jats:italic> 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.</jats:p>
  • Zugangsstatus: Freier Zugang