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DNA methylation as ...
DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
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- Kular, L (author)
- Karolinska Institutet
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Liu, Y (author)
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Ruhrmann, S (author)
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- Zheleznyakova, G (author)
- Karolinska Institutet
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- Marabita, F (author)
- Karolinska Institutet
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- Gomez-Cabrero, D (author)
- Karolinska Institutet
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- James, T (author)
- Karolinska Institutet
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- Ewing, E (author)
- Karolinska Institutet
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Linden, M (author)
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Gornikiewicz, B (author)
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Aeinehband, S (author)
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- Stridh, P (author)
- Karolinska Institutet
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Link, J (author)
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Andlauer, TFM (author)
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Gasperi, C (author)
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Wiendl, H (author)
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Zipp, F (author)
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Gold, R (author)
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Tackenberg, B (author)
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Weber, F (author)
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Hemmer, B (author)
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Strauch, K (author)
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Heilmann-Heimbach, S (author)
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Rawal, R (author)
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Schminke, U (author)
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Schmidt, CO (author)
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Kacprowski, T (author)
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Franke, A (author)
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Laudes, M (author)
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Dilthey, AT (author)
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Celius, EG (author)
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Sondergaard, HB (author)
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- Tegner, J (author)
- Karolinska Institutet
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Harbo, HF (author)
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Oturai, AB (author)
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Olafsson, S (author)
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Eggertsson, HP (author)
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Halldorsson, BV (author)
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Hjaltason, H (author)
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Olafsson, E (author)
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Jonsdottir, I (author)
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Stefansson, K (author)
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- Olsson, T (author)
- Karolinska Institutet
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- Piehl, F (author)
- Karolinska Institutet
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- Ekstrom, TJ (author)
- Karolinska Institutet
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- Kockum, I (author)
- Karolinska Institutet
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Feinberg, AP (author)
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- Jagodic, M (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2018-06-19
- 2018
- English.
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2397-
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https://doi.org/10.1...
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Abstract
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- 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.
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Kular, L
-
Liu, Y
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Ruhrmann, S
-
Zheleznyakova, G
-
Marabita, F
-
Gomez-Cabrero, D
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show more...
-
James, T
-
Ewing, E
-
Linden, M
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Gornikiewicz, B
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Aeinehband, S
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Stridh, P
-
Link, J
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Andlauer, TFM
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Gasperi, C
-
Wiendl, H
-
Zipp, F
-
Gold, R
-
Tackenberg, B
-
Weber, F
-
Hemmer, B
-
Strauch, K
-
Heilmann-Heimbac ...
-
Rawal, R
-
Schminke, U
-
Schmidt, CO
-
Kacprowski, T
-
Franke, A
-
Laudes, M
-
Dilthey, AT
-
Celius, EG
-
Sondergaard, HB
-
Tegner, J
-
Harbo, HF
-
Oturai, AB
-
Olafsson, S
-
Eggertsson, HP
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Halldorsson, BV
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Hjaltason, H
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Olafsson, E
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Jonsdottir, I
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Stefansson, K
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Olsson, T
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Piehl, F
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Ekstrom, TJ
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Kockum, I
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Feinberg, AP
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Jagodic, M
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show less...
- Articles in the publication
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Nature communica ...
- By the university
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Karolinska Institutet