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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.


ABSTRACT: 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?

SUBMITTER: Kular L 

PROVIDER: S-EPMC6008330 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.

Kular Lara L   Liu Yun Y   Ruhrmann Sabrina S   Zheleznyakova Galina G   Marabita Francesco F   Gomez-Cabrero David D   James Tojo T   Ewing Ewoud E   Lindén Magdalena M   Górnikiewicz Bartosz B   Aeinehband Shahin S   Stridh Pernilla P   Link Jenny J   Andlauer Till F M TFM   Gasperi Christiane C   Wiendl Heinz H   Zipp Frauke F   Gold Ralf R   Tackenberg Björn B   Weber Frank F   Hemmer Bernhard B   Strauch Konstantin K   Heilmann-Heimbach Stefanie S   Rawal Rajesh R   Schminke Ulf U   Schmidt Carsten O CO   Kacprowski Tim T   Franke Andre A   Laudes Matthias M   Dilthey Alexander T AT   Celius Elisabeth G EG   Søndergaard Helle B HB   Tegnér Jesper J   Harbo Hanne F HF   Oturai Annette B AB   Olafsson Sigurgeir S   Eggertsson Hannes P HP   Halldorsson Bjarni V BV   Hjaltason Haukur H   Olafsson Elias E   Jonsdottir Ingileif I   Stefansson Kari K   Olsson Tomas T   Piehl Fredrik F   Ekström Tomas J TJ   Kockum Ingrid I   Feinberg Andrew P AP   Jagodic Maja M  

Nature communications 20180619 1


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 change  ...[more]

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