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

Abstract

ObjectiveEpigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients.MethodsPeripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti‐cyclic citrullinated protein). Fluorescence‐activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome‐wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators.ResultsDifferential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type–specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified.ConclusionMethylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.

Inflammatory cytokines shape a changing DNA methylome in monocytes mirroring disease activity in rheumatoid arthritis

“…However, the finding of a robust and consistent correlation between methylation and DAS28 in those peripheral blood monocytes is of great value since it constitutes a less invasive approach to obtain biological samples from patients with RA. A previous study revealed that the hypomethylation of the CYP2E1 promoter in monocytes of patients with RA correlated to RA activity 23. By analysing our own data, we were also able to detect hypomethylation of the CYP2E1 promoter region.…”

“…Interestingly, the methylation profiles of both hypo.HA and hyper.HA CpG sites were highly similar between remission patients and healthy controls in an unsupervised representation (figure 2B and online supplementary figure 2C). We also inspected a DNA methylation dataset of monocytes of a cohort of patients with RA from a previously published study 23. By comparing their data and ours, we observed the same trend of changes in the methylomes in connexion with disease activity (see online supplementary figure 2D), despite that the patients with RA from Mok et al were classified using a different marker of disease activity, Clinical Disease Activity Index (CDAI).…”

PTP Inhibitor XIX Inhibits DUSP22 by Conformational Change

“…The involvement of DUSP22 as a negative regulator for the development of autoimmunity and Alzheimer's disease has been reported . Recently, the positive engagement of DUSP22 in the erosive disease among rheumatoid arthritis (RA) was suggested . Hypomethylation, observed among RA patients with erosive disease, leads to increased mRNA expression of DUSP22 , implying that DUSP22 could be involved in RA.…”

Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis

“…AZU1, LTBR, and RTEL1 are hypomethylated and involved in the autoimmune signaling cascade, indicating potential roles as epigenetic susceptibility markers (Wang et al, 2018). Hypomethylation of CYP2E1 is associated with disease activity and can be used as a disease activity marker (Mok et al, 2018). CD1C, TNFSF10, C6ORF10, and UBASH3A have the potential to be used as RA risk markers (Julia et al, 2017;Anaparti et al, 2019;Guderud et al, 2020).…”