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Background  Although 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.    Methods  Total 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.    Results  This 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.    Conclusions  The 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 material  The online version of this article (doi:10.1186/s13148-017-0371-1) contains supplementary material, which is available to authorized users.

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