DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.
DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.
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DOI：
10.1038/s41467-018-04732-5
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发表时间：
2018-06-19
影响因子：
16.6
通讯作者：
Jagodic M
中科院分区：
文献类型：
--
作者：
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
人类白细胞抗原（HLA）单倍型DRB 1 *15：01是多发性硬化症（MS）的主要危险因素。在这里，我们发现DRB 1 *15：01是低甲基化的，主要在DRB 1 *15：01携带者的单核细胞中表达。一个差异甲基化区域（DMR）包括HLA-DRB 1外显子2特别受到影响，并显示甲基化敏感的调节特性在体外。因果推断和孟德尔随机化提供了HLA变体通过改变HLA-DRB 1表达的HLA-DRB 1 DMR的变化介导MS风险的证据。对14，259例病例和171，347例对照的荟萃分析证实，这些变异赋予了DRB 1 *15：01的风险，并在该地区所有MS相关变异的条件下确定了保护性变异（rs 9267649，p < 3.32 × 10−8，比值比= 0.86）。rs 9267649与HLA-DRB 1 DMR处DNA甲基化增加和HLA-DRB 1表达减少相关，表明DRB 1 *15：01效应的调节。我们的综合方法提供了深入了解MS易感性的分子机制，并提出了针对甲基化介导的主要风险基因调控的假定治疗策略。人类白细胞抗原（HLA）单倍型DRB 1 *15：01是多发性硬化症（MS）的主要危险因素。 在这里，作者发现HLA-DRB 1基因的DNA甲基化介导了DRB 1 *15：01和保护性HLA变体对HLA-DRB 1表达和MS风险的影响。
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. The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.
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影响因子：
3.7
作者：
Alcina A;Abad-Grau Mdel M;Fedetz M;Izquierdo G;Lucas M;Fernández O;Ndagire D;Catalá-Rabasa A;Ruiz A;Gayán J;Delgado C;Arnal C;Matesanz F
通讯作者：
Matesanz F
影响因子：
4.3
作者：
Dilthey, Alexander;Leslie, Stephen;McVean, Gil
通讯作者：
McVean, Gil
DOI：
10.1161/atvbaha.111.240549
发表时间：
2012-06-01
影响因子：
8.7
作者：
Chernogubova, Ekaterina;Strawbridge, Rona;van 't Hooft, Ferdinand M.
通讯作者：
van 't Hooft, Ferdinand M.
DOI：
10.1007/s00103-012-1492-5
发表时间：
2012-06-01
影响因子：
1.7
作者：
Berger, K.
通讯作者：
Berger, K.
影响因子：
2.7
作者：
ALLEN, M;SANDBERGWOLLHEIM, M;GYLLENSTEN, U
通讯作者：
GYLLENSTEN, U