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

Lara Kular; Yun Liu; Sabrina Ruhrmann; Galina Zheleznyakova; Francesco Marabita; David Gomez-Cabrero; Tojo James; Ewoud Ewing; Magdalena Lindén; Bartosz Górnikiewicz; Shahin Aeinehband; Pernilla Stridh; Jenny Link; Till F.M. Andlauer; Christiane Gasperi; Heinz Wiendl; Frauke Zipp; Ralf Gold; Björn Tackenberg; Frank Weber; Bernhard Hemmer; Konstantin Strauch; Stefanie Heilmann-Heimbach; Rajesh Rawal; Ulf Schminke; Carsten O. Schmidt; Tim Kacprowski; Andre Franke; Matthias Laudes; Alexander T. Dilthey; Elisabeth G. Celius; Helle B. Søndergaard; Jesper Tegnér; Hanne F. Harbo; Annette B. Oturai; Sigurgeir Olafsson; Hannes P. Eggertsson; Bjarni V. Halldorsson; Haukur Hjaltason; Elias Olafsson; Ingileif Jonsdottir; Kari Stefansson; Tomas Olsson; Fredrik Piehl; Tomas J. Ekström; Ingrid Kockum; Andrew P. Feinberg; Maja Jagodic

doi:10.1038/s41467-018-04732-5

DNA methylation as a mediator of HLA-DRB115:01* and a protective variant in multiple sclerosis

Lara Kular, Yun Liu, Sabrina Ruhrmann, Galina Zheleznyakova, Francesco Marabita, David Gomez-Cabrero, Tojo James, Ewoud Ewing, Magdalena Lindén, Bartosz Górnikiewicz, Shahin Aeinehband, Pernilla Stridh, Jenny Link, Till F.M. Andlauer, Christiane Gasperi, Heinz Wiendl, Frauke Zipp, Ralf Gold, Björn Tackenberg, Frank WeberBernhard Hemmer, Konstantin Strauch, Stefanie Heilmann-Heimbach, Rajesh Rawal, Ulf Schminke, Carsten O. Schmidt, Tim Kacprowski, Andre Franke, Matthias Laudes, Alexander T. Dilthey, Elisabeth G. Celius, Helle B. Søndergaard, Jesper Tegnér, Hanne F. Harbo, Annette B. Oturai, Sigurgeir Olafsson, Hannes P. Eggertsson, Bjarni V. Halldorsson, Haukur Hjaltason, Elias Olafsson, Ingileif Jonsdottir, Kari Stefansson, Tomas Olsson, Fredrik Piehl, Tomas J. Ekström, Ingrid Kockum, Andrew P. Feinberg^*, Maja Jagodic

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

49 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	2397
Tidsskrift	Nature Communications
Vol/bind	9
Sider (fra-til)	1-15
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-04732-5
Status	Udgivet - 2018

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10.1038/s41467-018-04732-5Licens: CC BY

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Citationsformater

Kular, L., Liu, Y., Ruhrmann, S., Zheleznyakova, G., Marabita, F., Gomez-Cabrero, D., James, T., Ewing, E., Lindén, M., Górnikiewicz, B., Aeinehband, S., Stridh, P., Link, J., Andlauer, T. F. M., Gasperi, C., Wiendl, H., Zipp, F., Gold, R., Tackenberg, B., ... Jagodic, M. (2018). DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications, 9, 1-15. [2397]. https://doi.org/10.1038/s41467-018-04732-5

Kular, L, Liu, Y, Ruhrmann, S, Zheleznyakova, G, Marabita, F, Gomez-Cabrero, D, James, T, Ewing, E, Lindén, M, Górnikiewicz, B, Aeinehband, S, Stridh, P, Link, J, Andlauer, TFM, Gasperi, C, Wiendl, H, Zipp, F, Gold, R, Tackenberg, B, Weber, F, Hemmer, B, Strauch, K, Heilmann-Heimbach, S, Rawal, R, Schminke, U, Schmidt, CO, Kacprowski, T, Franke, A, Laudes, M, Dilthey, AT, Celius, EG, Søndergaard, HB, Tegnér, J, Harbo, HF, Oturai, AB, Olafsson, S, Eggertsson, HP, Halldorsson, BV, Hjaltason, H, Olafsson, E, Jonsdottir, I, Stefansson, K, Olsson, T, Piehl, F, Ekström, TJ, Kockum, I, Feinberg, AP & Jagodic, M 2018, 'DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis', Nature Communications, bind 9, 2397, s. 1-15. https://doi.org/10.1038/s41467-018-04732-5

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

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. ",

author = "Lara Kular and Yun Liu and Sabrina Ruhrmann and Galina Zheleznyakova and Francesco Marabita and David Gomez-Cabrero and Tojo James and Ewoud Ewing and Magdalena Lind{\'e}n and Bartosz G{\'o}rnikiewicz and Shahin Aeinehband and Pernilla Stridh and Jenny Link and Andlauer, {Till F.M.} and Christiane Gasperi and Heinz Wiendl and Frauke Zipp and Ralf Gold and Bj{\"o}rn Tackenberg and Frank Weber and Bernhard Hemmer and Konstantin Strauch and Stefanie Heilmann-Heimbach and Rajesh Rawal and Ulf Schminke and Schmidt, {Carsten O.} and Tim Kacprowski and Andre Franke and Matthias Laudes and Dilthey, {Alexander T.} and Celius, {Elisabeth G.} and S{\o}ndergaard, {Helle B.} and Jesper Tegn{\'e}r and Harbo, {Hanne F.} and Oturai, {Annette B.} and Sigurgeir Olafsson and Eggertsson, {Hannes P.} and Halldorsson, {Bjarni V.} and Haukur Hjaltason and Elias Olafsson and Ingileif Jonsdottir and Kari Stefansson and Tomas Olsson and Fredrik Piehl and Ekstr{\"o}m, {Tomas J.} and Ingrid Kockum and Feinberg, {Andrew P.} and Maja Jagodic",

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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

PY - 2018

Y1 - 2018

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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