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 < 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.

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

“…Overall, the PBMC-based methylomes of the 45 MS discordant MZ twins were highly similar, as the mean within-pair β -value differences were very small (<0.05). None of the MS-DMPs observed in our study have previously been reported by other EWAS for MS [19][20][21][22][23][24][25] .…”

“…Since these other studies used genetically unmatched cases and controls [19][20][21][22][23][24][25] , the large methylation differences observed by them might mainly be driven by genetic variation.…”

“…Thus far, several epigenome-wide association studies (EWAS) for MS have been carried out [19][20][21][22][23][24][25] , and a number of differentially methylated CpG positions (DMPs) have been reported, including DMPs in the HLA-DRB1 locus. However, even though these studies used the same array platform (i.e.…”

Environmental and genetic risk factors for MS: an integrated review

“…While several HLA Class II and I alleles contribute to MS susceptibility, the main one is carriage of the HLA DRB15:01 haplotype (odds ratio (OR) of ~3). This gene variant is carried by 25–30% of the population in northern Europe and the USA.…”

“…Autoproliferation of Th1 lymphocytes appears to be elevated in HLA‐DR15 ‐positive individuals and mediated by memory B cells in a HLA‐DR‐dependent manner . Interestingly, the DRB15:01 gene is epigenetically regulated, leading to increased expression and antigen presentation …”