TY - JOUR
T1 - DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis
AU - Kular, Lara
AU - Liu, Yun
AU - Ruhrmann, Sabrina
AU - Zheleznyakova, Galina
AU - Marabita, Francesco
AU - Gomez-Cabrero, David
AU - James, Tojo
AU - Ewing, Ewoud
AU - Lindén, Magdalena
AU - Górnikiewicz, Bartosz
AU - Aeinehband, Shahin
AU - Stridh, Pernilla
AU - Link, Jenny
AU - Andlauer, Till F.M.
AU - Gasperi, Christiane
AU - Wiendl, Heinz
AU - Zipp, Frauke
AU - Gold, Ralf
AU - Tackenberg, Björn
AU - Weber, Frank
AU - Hemmer, Bernhard
AU - Strauch, Konstantin
AU - Heilmann-Heimbach, Stefanie
AU - Rawal, Rajesh
AU - Schminke, Ulf
AU - Schmidt, Carsten O.
AU - Kacprowski, Tim
AU - Franke, Andre
AU - Laudes, Matthias
AU - Dilthey, Alexander T.
AU - Celius, Elisabeth G.
AU - Søndergaard, Helle B.
AU - Tegnér, Jesper
AU - Harbo, Hanne F.
AU - Oturai, Annette B.
AU - Olafsson, Sigurgeir
AU - Eggertsson, Hannes P.
AU - Halldorsson, Bjarni V.
AU - Hjaltason, Haukur
AU - Olafsson, Elias
AU - Jonsdottir, Ingileif
AU - Stefansson, Kari
AU - Olsson, Tomas
AU - Piehl, Fredrik
AU - Ekström, Tomas J.
AU - Kockum, Ingrid
AU - Feinberg, Andrew P.
AU - Jagodic, Maja
N1 - Funding Information:
This work was supported by grants from the Swedish Research Council, the Swedish Association for Persons with Neurological Disabilities, the Swedish Brain Foundation, the Swedish MS Foundation, Petrus and Augusta Hedlunds Foundation, the Swedish AFA Insurance, Knut and Alice Wallenberg Foundation, the Stockholm County Council (ALF project), and AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration). A.P.F. received grant support from NIH (DP1 ES022579). L.K. was supported by fellowship from the Margaretha af Ugglas Foundation. D.G.-C. and J.T. were supported by EU FP7 306000 STATegra. Y.L. was supported in part by the National Natural Science Foundation (grant no. 31471212).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04732-5
DO - 10.1038/s41467-018-04732-5
M3 - Article
C2 - 29921915
AN - SCOPUS:85048753233
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2397
ER -