Rheumatoid Arthritis Naive T Cells Share Hypermethylation Sites With Synoviocytes

Abstract

ObjectiveTo determine whether differentially methylated CpGs in synovium‐derived fibroblast‐like synoviocytes (FLS) of patients with rheumatoid arthritis (RA) were also differentially methylated in RA peripheral blood (PB) samples.MethodsFor this study, 371 genome‐wide DNA methylation profiles were measured using Illumina HumanMethylation450 BeadChips in PB samples from 63 patients with RA and 31 unaffected control subjects, specifically in the cell subsets of CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells.ResultsOf 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ naive T cells from RA PB compared to control PB. In analyses of a second set of CpG candidates based on single‐nucleotide polymorphisms from a genome‐wide association study of RA, 1 significantly hypermethylated CpG in CD4+ memory T cells and 18 significant CpGs (6 hypomethylated, 12 hypermethylated) in CD4+ naive T cells were found. A prediction score based on the hypermethylated FLS candidates had an area under the curve of 0.73 for association with RA case status, which compared favorably to the association of RA with the HLA–DRB1 shared epitope risk allele and with a validated RA genetic risk score.ConclusionFLS‐representative DNA methylation signatures derived from the PB may prove to be valuable biomarkers for the risk of RA or for disease status.

Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients

“…Our previous analysis in the same RA patient population identified predominantly hypomethylated candidate CpG sites in naïve and memory CD4+ T cells of patients compared to healthy controls (22). Comparisons of results from the current study of clinical phenotypes with the previous RA case-control study did not reveal significant overlap of differential methylation.…”

Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology

“…The presumption that only some particular immune cell-types are related to the pathogenesis of RA, have led to studies with methylation collected from sorted populations of leukocytes (e.g., 34–36 ). In a recent study by Rhead et al, some of us investigated differences in methylation patterns between RA cases and controls using data collected from sorted cells 36 . Particularly, methylation levels were collected from two sub-populations of CD4+ T cells (memory cells and naive cells; n=90, n=88), CD14+ monocytes (n=90), and CD19+ B cells (n=87).…”

“…We used a total of five methylation data sets, all of which were collected using the Illumina 450K human DNA methylation array and are available from the Gene Omnibus Database (GEO). In more details, we used 3 methylation data sets that were previously collected in RA studies: a whole-blood data set by Liu et al of 354 RA cases and 332 controls (GEO accession GSE42861) 19 , a CD4+ methylation data set of 12 RA cases and 12 controls with matching age and sex (for each RA patient, a control sample with matching age and sex was collected) by Guo et al (GEO accession GSE71841) 35 , and cell-sorted methylation data collected from 63 female RA patients and 31 female control subjects in CD4+ memory cells, CD4+ naive cells, CD14+ monocytes, and CD19+ B cells (a total of 371 samples across four cell sub-types; GEO accession GSE131989); these cell-sorted data were originally described by Rhead et al 36 . In addition, for replicating the association results with immune activity, we used another data set that was previously studied by Hannum et al in the context of aging rates (n=656; GEO accession GSE40279) 30 .…”

Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

“…Here, a substantial number of dysregulations forming part of the TNF‐Tg signature were found to parallel the TNF‐induced profiles at all 3 time points, with ∼85% for RNA and DNA methylation and 70% for H3K4 trimethylation. Of note, it would be interesting to see how many of the more than 5,000 hypermethylated RA synovial fibroblast CpGs, of which more than 1,000 were also hypermethylated in CD41 naive T cells from RA , link with the loci in the present study.…”