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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
- Liu, Y (author)
- Ruhrmann, S (author)
- show more...
- Linden, M (author)
- Gornikiewicz, B (author)
- Aeinehband, S (author)
- Link, J (author)
- Andlauer, TFM (author)
- Gasperi, C (author)
- Wiendl, H (author)
- Zipp, F (author)
- Gold, R (author)
- Tackenberg, B (author)
- Weber, F (author)
- Hemmer, B (author)
- Strauch, K (author)
- Heilmann-Heimbach, S (author)
- Rawal, R (author)
- Schminke, U (author)
- Schmidt, CO (author)
- Kacprowski, T (author)
- Franke, A (author)
- Laudes, M (author)
- Dilthey, AT (author)
- Celius, EG (author)
- Sondergaard, HB (author)
- Harbo, HF (author)
- Oturai, AB (author)
- Olafsson, S (author)
- Eggertsson, HP (author)
- Halldorsson, BV (author)
- Hjaltason, H (author)
- Olafsson, E (author)
- Jonsdottir, I (author)
- Stefansson, K (author)
- Feinberg, AP (author)
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- (creator_code:org_t)
- 2018-06-19
- 2018
- English.
- In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2397-
- Journal article (peer-reviewed)
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.
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- Kular, L
- Liu, Y
- Ruhrmann, S
- Zheleznyakova, G
- Marabita, F
- Gomez-Cabrero, D
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- James, T
- Ewing, E
- Linden, M
- Gornikiewicz, 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-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
- Halldorsson, BV
- Hjaltason, H
- Olafsson, E
- Jonsdottir, I
- Stefansson, K
- Olsson, T
- Piehl, F
- Ekstrom, TJ
- Kockum, I
- Feinberg, AP
- Jagodic, M
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