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Journal Article

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

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Andlauer,  Till F. M.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
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Weber,  Frank
Max Planck Institute of Psychiatry, Max Planck Society;
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41467_2018_Article_4732.pdf
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Citation

Kular, L., Liu, Y., Ruhrmann, S., Zheleznyakova, G., Marabita, F., Gomez-Cabrero, D., et al. (2018). DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. NATURE COMMUNICATIONS, 9: 2397. doi:10.1038/s41467-018-04732-5.


Cite as: https://hdl.handle.net/21.11116/0000-0003-5CBD-2
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.