Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04732-5
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Funding
- Swedish Research Council
- Swedish Association for Persons with Neurological Disabilities
- Swedish Brain Foundation
- Swedish MS Foundation
- Petrus and Augusta Hedlunds Foundation
- Swedish AFA Insurance
- Knut and Alice Wallenberg Foundation
- Stockholm County Council (ALF project)
- AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration)
- NIH [DP1 ES022579]
- Margaretha af Ugglas Foundation
- EU [306000]
- National Natural Science Foundation [31471212]
- German research foundation
- German MS competence network
- the EU project MultipleMS
- German Ministry for Education and Research (BMBF) as part of the German Competence Network Multiple Sclerosis (KKNMS) [01GI0916, 01GI0917]
- Helmholtz Zentrum Munchen-German Research Center for Environmental Health - BMBF
- State of Bavaria
- Munich Center of Health Sciences (MC-Health)
- Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- Heinz Nixdorf Foundation
- BMBF [01ER0816, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 0315540A]
- German Migraine and Headache Society (DMKG)
- Almirall
- AstraZeneca
- Berlin-Chemie
- Boehringer
- Boots Healthcare
- GlaxoSmithKline (GSK)
- Janssen-Cilag
- McNeil Pharma
- Merck Sharp Dohme (MSD)
- Pfizer
- Institute of Epidemiology and Social Medicine, University of Munster
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
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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.
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