GSTDTAP  > 资源环境科学
DOI10.1038/s41467-019-12828-9
DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis
Kular, Lara1; Liu, Yun2,3,4,5,6,7; Ruhrmann, Sabrina1; Zheleznyakova, Galina1; Marabita, Francesco1; Gomez-Cabrero, David8; James, Tojo1; Ewing, Ewoud1; Linden, Magdalena1; Gornikiewicz, Bartosz1; Aeinehband, Shahin1; Stridh, Pernilla1; Link, Jenny1; Andlauer, Till F. M.9,10,11; Gasperi, Christiane10,11; Wiendl, Heinz11,12; Zipp, Frauke11,13; Gold, Ralf11,14; Tackenberg, Bjoern11,15; Weber, Frank9,11; Hemmer, Bernhard10,11,16; Strauch, Konstantin17,18; Heilmann-Heimbach, Stefanie19,20; Rawal, Rajesh21; Schminke, Ulf22; Schmidt, Carsten O.23; Kacprowski, Tim24,25; Franke, Andre26; Laudes, Matthias27; Dilthey, Alexander T.28,29; Celius, Elisabeth G.30,31; Sondergaard, Helle B.32; Tegner, Jesper8,33; Harbo, Hanne F.30,34; Oturai, Annette B.32; Olafsson, Sigurgeir35; Eggertsson, Hannes P.35; Halldorsson, Bjarni V.35,36; Hjaltason, Haukur37,38; Olafsson, Elias37,38; Jonsdottir, Ingileif35,38,39; Stefansson, Kari35,38; Olsson, Tomas1; Piehl, Fredrik1; Ekstroem, Tomas J.1; Kockum, Ingrid1; Feinberg, Andrew P.2,3,4,5; Jagodic, Maja1
2019-10-23
发表期刊NATURE COMMUNICATIONS
ISSN2041-1723
出版年2018
卷号9
文章类型Article
语种英语
国家Sweden; USA; Peoples R China; Germany; England; Norway; Denmark; Saudi Arabia; Iceland
英文摘要

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.


领域资源环境
收录类别SCI-E
WOS记录号WOS:000435538500015
WOS关键词GENETIC RISK ; DIFFERENTIAL EXPRESSION ; WIDE ASSOCIATION ; LOCUS ; DISEASE ; MONOCYTES ; SUSCEPTIBILITY ; TRANSCRIPTION ; MACROPHAGES ; MICROGLIA
WOS类目Multidisciplinary Sciences
WOS研究方向Science & Technology - Other Topics
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文献类型期刊论文
条目标识符http://119.78.100.173/C666/handle/2XK7JSWQ/204611
专题资源环境科学
作者单位1.Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, S-17177 Stockholm, Sweden;
2.Johns Hopkins Univ, Ctr Epigenet, Baltimore, MD 21205 USA;
3.Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA;
4.Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA;
5.Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21205 USA;
6.Fudan Univ, Shanghai Med Coll, Key Lab Metab & Mol Med, Minist Educ, Shanghai 200032, Peoples R China;
7.Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200032, Peoples R China;
8.Karolinska Inst, Unit Computat Med, Dept Med, Ctr Mol Med, S-17177 Stockholm, Sweden;
9.Max Planck Inst Psychiat, D-80804 Munich, Germany;
10.Tech Univ Munich, Sch Med, Dept Neurol, Klinikum Rechts Isar, D-81675 Munich, Germany;
11.Tech Univ Munich, Klinikum Rechts Isar, German Competence Network Multiple Sclerosis KKNM, D-81675 Munich, Germany;
12.Univ Munster, Dept Neurol, Inst Translat Neurol, D-48149 Munster, Germany;
13.Johannes Gutenberg Univ Mainz, Univ Med Mainz, Dept Neurol, D-55122 Mainz, Germany;
14.Ruhr Univ Bochum, St Josef Hosp, Dept Neurol, D-44801 Bochum, Germany;
15.Marburg Univ, Neuroimmunol Ctr, D-35037 Marburg, Germany;
16.Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany;
17.Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany;
18.Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-80539 Munich, Germany;
19.Univ Bonn, Sch Med, Inst Human Genet, Univ Hosp Bonn, D-53113 Bonn, Germany;
20.Univ Bonn, Sch Med, Div Genom, Life & Brain Res Ctr, D-53113 Bonn, Germany;
21.Univ Munster, Inst Epidemiol & Social Med, D-48149 Munster, Germany;
22.Univ Med Greifswald, Dept Neurol, D-17489 Greifswald, Germany;
23.Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany;
24.Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17489 Greifswald, Germany;
25.Univ Med Greifswald, D-17489 Greifswald, Germany;
26.Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany;
27.Univ Kiel, Dept Internal Med 1, D-24105 Kiel, Germany;
28.Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England;
29.Heinrich Heine Univ Dusseldorf, Inst Med Microbiol & Hosp Hyg, D-40225 Dusseldorf, Germany;
30.Oslo Univ Hosp, Dept Neurol, N-0372 Oslo, Norway;
31.Univ Oslo, Inst Hlth & Soc, Fac Med, N-0450 Oslo, Norway;
32.Univ Copenhagen, Rigshosp, Dept Neurol, Danish Multiple Sclerosis Ctr, DK-2100 Copenhagen, Denmark;
33.King Abdullah Univ Sci & Technol, Biol & Environm Sci & Engn Div, Comp Elect & Math Sci & Engn Div, Thuwal 23955, Saudi Arabia;
34.Univ Oslo, Inst Clin Med, N-0450 Oslo, Norway;
35.Amgen Inc, DeCODE Genetics, IS-101 Reykjavik, Iceland;
36.Reykjavik Univ, Sch Sci & Engn, IS-101 Reykjavik, Iceland;
37.Natl Univ Iceland, Dept Neurol, Landspitali, IS-101 Reykjavik, Iceland;
38.Univ Iceland, Sch Hlth Sci, Fac Med, IS-101 Reykjavik, Iceland;
39.Natl Univ Hosp Iceland, Dept Immunol, Landspitali, IS-101 Reykjavik, Iceland
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Kular, Lara,Liu, Yun,Ruhrmann, Sabrina,et al. DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis[J]. NATURE COMMUNICATIONS,2019,9.
APA Kular, Lara.,Liu, Yun.,Ruhrmann, Sabrina.,Zheleznyakova, Galina.,Marabita, Francesco.,...&Jagodic, Maja.(2019).DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis.NATURE COMMUNICATIONS,9.
MLA Kular, Lara,et al."DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis".NATURE COMMUNICATIONS 9(2019).
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