PMID- 29921915
OWN - NLM
STAT- MEDLINE
DCOM- 20181226
LR  - 20220408
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Jun 19
TI  - DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in 
      multiple sclerosis.
PG  - 2397
LID - 10.1038/s41467-018-04732-5 [doi]
LID - 2397
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 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*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.
FAU - Kular, Lara
AU  - Kular L
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Liu, Yun
AU  - Liu Y
AD  - Center for Epigenetics, and Departments of Medicine, Biomedical Engineering and 
      Mental Health, Johns Hopkins University, Baltimore, MD, 21205, USA.
AD  - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education; 
      Department of Biochemistry and Molecular Biology, Fudan University Shanghai 
      Medical College, 200032, Shanghai, China.
FAU - Ruhrmann, Sabrina
AU  - Ruhrmann S
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Zheleznyakova, Galina
AU  - Zheleznyakova G
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Marabita, Francesco
AU  - Marabita F
AUID- ORCID: 0000-0001-6180-0106
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Gomez-Cabrero, David
AU  - Gomez-Cabrero D
AD  - Unit of Computational Medicine, Department of Medicine, Solna, Center for 
      Molecular Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
FAU - James, Tojo
AU  - James T
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Ewing, Ewoud
AU  - Ewing E
AUID- ORCID: 0000-0001-8644-366X
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Linden, Magdalena
AU  - Linden M
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Gornikiewicz, Bartosz
AU  - Gornikiewicz B
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Aeinehband, Shahin
AU  - Aeinehband S
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Stridh, Pernilla
AU  - Stridh P
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Link, Jenny
AU  - Link J
AUID- ORCID: 0000-0002-6134-9404
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Andlauer, Till F M
AU  - Andlauer TFM
AUID- ORCID: 0000-0002-2917-5889
AD  - Max Planck Institute of Psychiatry, 80804, Munich, Germany.
AD  - Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technische 
      Universitat Munchen, 81675, Munich, Germany.
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
FAU - Gasperi, Christiane
AU  - Gasperi C
AD  - Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technische 
      Universitat Munchen, 81675, Munich, Germany.
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
FAU - Wiendl, Heinz
AU  - Wiendl H
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
AD  - Department of Neurology with Institute of Translational Neurology, University of 
      Munster, 48149, Munster, Germany.
FAU - Zipp, Frauke
AU  - Zipp F
AUID- ORCID: 0000-0002-1231-1928
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
AD  - Department of Neurology, University Medicine Mainz, Johannes Gutenberg University 
      Mainz, 55122, Mainz, Germany.
FAU - Gold, Ralf
AU  - Gold R
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
AD  - Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44801, 
      Bochum, Germany.
FAU - Tackenberg, Bjorn
AU  - Tackenberg B
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
AD  - Neuroimmunology Center, Marburg University, 35037, Marburg, Germany.
FAU - Weber, Frank
AU  - Weber F
AD  - Max Planck Institute of Psychiatry, 80804, Munich, Germany.
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
FAU - Hemmer, Bernhard
AU  - Hemmer B
AD  - Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technische 
      Universitat Munchen, 81675, Munich, Germany.
AD  - German Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, 
      Technische Universitat Munchen, 81675, Munich, Germany.
AD  - Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
FAU - Strauch, Konstantin
AU  - Strauch K
AD  - Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, Neuherberg, Germany 
      and Institute of Medical Informatics, Biometry, and Epidemiology, Chair of 
      Genetic Epidemiology, Ludwig-Maximilians-Universitat, 80539, Munich, Germany.
FAU - Heilmann-Heimbach, Stefanie
AU  - Heilmann-Heimbach S
AD  - Institute of Human Genetics, University Hospital Bonn and Division of Genomics, 
      Life & Brain Research Centre, University of Bonn School of Medicine, 53113, Bonn, 
      Germany.
FAU - Rawal, Rajesh
AU  - Rawal R
AD  - Institute of Epidemiology and Social Medicine, University of Munster, 48149, 
      Munster, Germany.
FAU - Schminke, Ulf
AU  - Schminke U
AD  - Department of Neurology, University Medicine Greifswald, 17489, Greifswald, 
      Germany.
FAU - Schmidt, Carsten O
AU  - Schmidt CO
AD  - Institute for Community Medicine, University Medicine Greifswald, 17489, 
      Greifswald, Germany.
FAU - Kacprowski, Tim
AU  - Kacprowski T
AUID- ORCID: 0000-0002-5393-2413
AD  - Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt 
      University and University Medicine Greifswald, 17489, Greifswald, Germany.
FAU - Franke, Andre
AU  - Franke A
AUID- ORCID: 0000-0003-1530-5811
AD  - Institute of Clinical Molecular Biology, Kiel University, 24105, Kiel, Germany.
FAU - Laudes, Matthias
AU  - Laudes M
AD  - Department I of Internal Medicine, Kiel University, 24105, Kiel, Germany.
FAU - Dilthey, Alexander T
AU  - Dilthey AT
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, 
      UK.
AD  - Institute of Medical Microbiology and Hospital Hygiene Heinrich-Heine-University 
      Dusseldorf, 40225, Dusseldorf, Germany.
FAU - Celius, Elisabeth G
AU  - Celius EG
AD  - Department of Neurology, Oslo University Hospital, 0372, Oslo, Norway.
AD  - Institute of Health and Society, Faculty of Medicine, University of Oslo, 0450, 
      Olso, Norway.
FAU - Sondergaard, Helle B
AU  - Sondergaard HB
AD  - Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, 
      University of Copenhagen, 2100, Copenhagen, Denmark.
FAU - Tegner, Jesper
AU  - Tegner J
AD  - Unit of Computational Medicine, Department of Medicine, Solna, Center for 
      Molecular Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
AD  - Biological and Environmental Sciences and Engineering Division, Computer, 
      Electrical and Mathematical Sciences and Engineering Division, King Abdullah 
      University of Science and Technology, Thuwal, 23955, Saudi Arabia.
FAU - Harbo, Hanne F
AU  - Harbo HF
AD  - Department of Neurology, Oslo University Hospital, 0372, Oslo, Norway.
AD  - Institute of Clinical Medicine, University of Oslo, 0450, Oslo, Norway.
FAU - Oturai, Annette B
AU  - Oturai AB
AD  - Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, 
      University of Copenhagen, 2100, Copenhagen, Denmark.
FAU - Olafsson, Sigurgeir
AU  - Olafsson S
AD  - deCODE genetics/Amgen Inc, 101, Reykjavik, Iceland.
FAU - Eggertsson, Hannes P
AU  - Eggertsson HP
AUID- ORCID: 0000-0002-1674-9978
AD  - deCODE genetics/Amgen Inc, 101, Reykjavik, Iceland.
FAU - Halldorsson, Bjarni V
AU  - Halldorsson BV
AUID- ORCID: 0000-0003-0756-0767
AD  - deCODE genetics/Amgen Inc, 101, Reykjavik, Iceland.
AD  - School of Science and Engineering, Reykjavik University, 101, Reykjavik, Iceland.
FAU - Hjaltason, Haukur
AU  - Hjaltason H
AD  - Department of Neurology, Landspitali, The National University of Iceland, 101, 
      Reykjavik, Iceland.
AD  - Faculty of Medicine, School of Health Sciences, University of Iceland, 101, 
      Reykjavik, Iceland.
FAU - Olafsson, Elias
AU  - Olafsson E
AD  - Department of Neurology, Landspitali, The National University of Iceland, 101, 
      Reykjavik, Iceland.
AD  - Faculty of Medicine, School of Health Sciences, University of Iceland, 101, 
      Reykjavik, Iceland.
FAU - Jonsdottir, Ingileif
AU  - Jonsdottir I
AD  - deCODE genetics/Amgen Inc, 101, Reykjavik, Iceland.
AD  - Faculty of Medicine, School of Health Sciences, University of Iceland, 101, 
      Reykjavik, Iceland.
AD  - Department of Immunology, Landspitali, The National University Hospital of 
      Iceland, 101, Reykjavik, Iceland.
FAU - Stefansson, Kari
AU  - Stefansson K
AD  - deCODE genetics/Amgen Inc, 101, Reykjavik, Iceland.
AD  - Faculty of Medicine, School of Health Sciences, University of Iceland, 101, 
      Reykjavik, Iceland.
FAU - Olsson, Tomas
AU  - Olsson T
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Piehl, Fredrik
AU  - Piehl F
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Ekstrom, Tomas J
AU  - Ekstrom TJ
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Kockum, Ingrid
AU  - Kockum I
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden.
FAU - Feinberg, Andrew P
AU  - Feinberg AP
AUID- ORCID: 0000-0002-8364-1991
AD  - Center for Epigenetics, and Departments of Medicine, Biomedical Engineering and 
      Mental Health, Johns Hopkins University, Baltimore, MD, 21205, USA. 
      afeinberg@jhu.edu.
FAU - Jagodic, Maja
AU  - Jagodic M
AD  - Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska 
      Institutet, 171 77, Stockholm, Sweden. Maja.Jagodic@ki.se.
LA  - eng
GR  - DP1 ES022579/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180619
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*15:01 antigen)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Cells, Cultured
MH  - Cohort Studies
MH  - *DNA Methylation
MH  - Female
MH  - Gene Expression Regulation
MH  - Genetic Predisposition to Disease/*genetics
MH  - HLA-DRB1 Chains/*genetics
MH  - Humans
MH  - Male
MH  - Meta-Analysis as Topic
MH  - Middle Aged
MH  - Multiple Sclerosis/*genetics/immunology/pathology
MH  - *Polymorphism, Single Nucleotide
MH  - Risk Factors
MH  - Young Adult
PMC - PMC6008330
COIS- Sigurgeir Olafsson, Hannes P. Eggertsson, Bjarni V. Halldorsson, Ingileif 
      Jonsdottir and Kari Stefanssonare employees of deCODE genetics/Amgen Inc at the 
      time work related to this study was carried out.H.F. Harbo has received honoraria 
      for advice and lecturing from Biogen, Genzyme, Merck, Novartis,Sanofi-Aventis and 
      Teva. She has received modest unrestricted research grant for research 
      fromNovartis. B. Tackenberg received personal speaker honoraria and consultancy 
      fees as a speaker andadvisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, 
      Merck Serono, Novartis, Octapharma,Roche, Sanofi Genzyme, TEVA und UCB Pharma. 
      His University received unrestricted research grantsfrom Biogen-idec, Novartis, 
      TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, SanofiGenzyme and UCB 
      Pharma. B. Hemmer has served on scientific advisory boards for F. 
      Hoffmann-LaRoche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC 
      member for AllergyCare and TGtherapeutics; he or his institution have received 
      speaker honoraria from Biogen Idec, TevaNeuroscience, Merck Serono, Medimmune, 
      Novartis, Desitin, and F. Hoffmann-La Roche Ltd; hisinstitution has received 
      research support from Chugai Pharmaceuticals and Biogen; holds part of 
      two patents; one for the detection of antibodies against KIR4.1 in a 
      subpopulation of MS patients and one for genetic determinants of neutralizing 
      antibodies to interferon beta. The remaining authors declare no competing interests.
EDAT- 2018/06/21 06:00
MHDA- 2018/12/27 06:00
PMCR- 2018/06/19
CRDT- 2018/06/21 06:00
PHST- 2018/01/09 00:00 [received]
PHST- 2018/05/17 00:00 [accepted]
PHST- 2018/06/21 06:00 [entrez]
PHST- 2018/06/21 06:00 [pubmed]
PHST- 2018/12/27 06:00 [medline]
PHST- 2018/06/19 00:00 [pmc-release]
AID - 10.1038/s41467-018-04732-5 [pii]
AID - 4732 [pii]
AID - 10.1038/s41467-018-04732-5 [doi]
PST - epublish
SO  - Nat Commun. 2018 Jun 19;9(1):2397. doi: 10.1038/s41467-018-04732-5.