Abstract
The pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4+ T cells of relapsing–remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39. This study aimed to investigate the DNA methylation profiles of the CD4+ T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A, SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block; however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.
Highlights
IntroductionWe have previously assessed DNA methylation in the CD4+ T cells of relapsing–remitting (RR) multiple sclerosis (MS) patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39
The pathology of progressive multiple sclerosis (MS) is poorly understood
In CD4+ T cells, we found a striking methylation signal located at the MHC locus with peaks at HLA-DRB1 and RNF39 present in RRMS patients compared to healthy c ontrols[8,11]
Summary
We have previously assessed DNA methylation in the CD4+ T cells of relapsing–remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39. A more recent study investigated the interplay between DNA methylation and genetic background in the DRB1 region and found that MS patients who were carriers of the high risk HLA-DRB1 15*01 allele had significantly lower DNA methylation at HLA-DRB1 compared to those who were not carriers. This was the case in monocytes, B cells and both CD4+ and CD8+ T cells. This is important because disease progression and accompanying disability may not be targeted by current therapies
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