Abstract
BackgroundMethotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4+ T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing.ResultsWe found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations. Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to predict treatment outcome in RA patients when measured in bulk T cells. Furthermore, several of the genes, including STAT3, annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX.ConclusionWe detected CpG sites that were associated with MTX treatment in CD4+ naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome.
Highlights
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease leading to joint destruction, disability, systemic complications, shorter life expectancy and increased socioeconomic costs
We investigated whether genes implicated through Single nucleotide polymorphisms (SNPs) found to be associated with MTX response in either RA [13, 14] or Juvenile idiopathic arthritis (JIA) [15] were among the genes annotated to CpG sites (CpGs) showing differential DNA methylation after MTX treatment in the RA patients (Table 2)
By using multiplexed reduced representation bisulfite sequencing (mRRBS), we identified significant DNA methylation changes associated with MTX treatment, and these changes were distinct in naïve and memory CD4+ T cells from RA patients
Summary
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease leading to joint destruction, disability, systemic complications, shorter life expectancy and increased socioeconomic costs. The RA incidence in Norway is 25 per 100 000 per year [2], and the majority of these patients will start treatment with one or more disease-modifying antirheumatic drugs (DMARDs), with the most extensively used being methotrexate (MTX) [2]. A treat-to-target approach, consisting of frequent clinical consultations and a quicker introduction of more potent drugs to reduce the disease activity, has been introduced [7]. Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4+ T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing
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