Opin vísindi

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

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


Title: DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
Author: Kular, Lara
Liu, Yun
Ruhrmann, Sabrina
Zheleznyakova, Galina
Marabita, Francesco
Gomez-Cabrero, David
James, Tojo
Ewing, Ewoud
Lindén, Magdalena
Górnikiewicz, Bartosz
... 38 more authors Show all authors
Date: 2018-06-19
Language: English
Scope: 2397
University/Institute: Háskólinn í Reykjavík
Reykjavik University
Háskóli Íslands
University of Iceland
School: Tækni og Verkfræðideild (HR)
School of Science and Engineering (RU)
Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Nature Communications;9(1)
ISSN: 2041-1723 (eISSN)
DOI: 10.1038/s41467-018-04732-5
Subject: Multiple sclerosis; DNA methylation; Epigenomics; MS sjúkdómur; DNA kjarnsýra; Erfðarannsóknir
URI: https://hdl.handle.net/20.500.11815/1306

Show full item record

Citation:

Kular, L., Liu, Y., Ruhrmann, S., Zheleznyakova, G., Marabita, F., Gomez-Cabrero, D., … Jagodic, M. (2018). DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications, 9(1), 2397. https://doi.org/10.1038/s41467-018-04732-5

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.

Description:

These authors contributed equally: Lara Kular, Yun Liu, Ingrid Kockum, Andrew P. Feinberg, Maja Jagodic.

Rights:

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Files in this item

This item appears in the following Collection(s)