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DOI | 10.1038/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
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ISSN | 2041-1723 |
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 |
URL | 查看原文 |
引用统计 | |
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 |
推荐引用方式 GB/T 7714 | 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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