Differential methylation at MHC in CD4+ T cells is associated with multiple sclerosis independently of HLA-DRB1

Abstract

BackgroundAlthough many genetic variants have been associated with multiple sclerosis (MS) risk, they do not explain all the disease risk and there remains uncertainty as to how these variants contribute to disease. DNA methylation is an epigenetic mechanism that can influence gene expression and has the potential to mediate the effects of environmental factors on MS. In a previous study, we found a differentially methylation region (DMR) at MHC HLA-DRB1 that was associated within relapsing-remitting MS (RRMS) patients in CD4+ T cells. This study aimed to confirm this earlier finding in an independent RRMS cohort of treatment-naïve female patients.MethodsTotal genomic DNA was extracted from CD4+ T cells of 28 female RRMS and 22 age-matched healthy controls subjects. DNA was bisulfite-converted and hybridised to Illumina 450K arrays. Beta values for all CpGs were analysed using the DMPFinder function in the MINFI program, and a follow-up prioritisation process was applied to identify the most robust MS-associated DMRs.ResultsThis study confirmed our previous findings of a hypomethylated DMR at HLA-DRB1 and a hypermethylated DMR at HLA-DRB5 in this RRMS patient cohort. In addition, we identified a large independent DMR at MHC, whereby 11 CpGs in RNF39 were hypermethylated in MS cases compared to controls (max. ∆beta = 0.19, P = 2.1 × 10−4). We did not find evidence that SNP genotype was influencing the DMR in this cohort. A smaller MHC DMR was also identified at HCG4B, and two non-MHC DMRs at PM20D1 on chr1 and ERICH1 on chr8 were also identified.ConclusionsThe findings from this study confirm our previous results of a DMR at HLA-DRB1 and also suggest hypermethylation in an independent MHC locus, RNF39, is associated with MS. Taken together, our results highlight the importance of epigenetic factors at the MHC locus in MS independent of treatment, age and sex. Prospective studies are now required to discern whether methylation at MHC is involved in influencing risk of disease onset or whether the disease itself has altered the methylation profile.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0371-1) contains supplementary material, which is available to authorized users.

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] .…”

“…However, those MS EWAS studies observed much larger methylation differences and used selection criteria for MS-DMPs of absolute mean β -value differences >0.05 19 , or even >0.10 [20][21][22][23] .…”

“…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

“…DNA methylation is probably the best explored of the three main epigenetic processes, and aberrant methylation in gene regulator regions may underlie processes involved in MS onset . While methylation changes have been reported in MS at HLA‐DRB1 in CD4 + but not CD8 + T cells, in brains, and in relapsing‐remitting versus primary progressive MS, it is unclear if these changes are drivers or responses to the disease.…”