Rheumatoid arthritis-associated DNA methylation sites in peripheral blood mononuclear cells.

Abstract

To identify novel DNA methylation sites significant for rheumatoid arthritis (RA) and comprehensively understand their underlying pathological mechanism. We performed (1) genome-wide DNA methylation and mRNA expression profiling in peripheral blood mononuclear cells from RA patients and health controls; (2) correlation analysis and causal inference tests for DNA methylation and mRNA expression data; (3) differential methylation genes regulatory network construction; (4) validation tests of 10 differential methylation positions (DMPs) of interest and corresponding gene expressions; (5) correlation between <i>PARP9</i> methylation and its mRNA expression level in Jurkat cells and T cells from patients with RA; (6) testing the pathological functions of <i>PARP9</i> in Jurkat cells. A total of 1046 DNA methylation positions were associated with RA. The identified DMPs have regulatory effects on mRNA expressions. Causal inference tests identified six DNA methylation-mRNA-RA regulatory chains (eg, cg00959259-PARP9-RA). The identified DMPs and genes formed an interferon-inducible gene interaction network (eg, <i>MX1</i>, <i>IFI44L</i>, <i>DTX3L</i> and <i>PARP9</i>). Key DMPs and corresponding genes were validated their differences in additional samples. Methylation of PARP9 was correlated with mRNA level in Jurkat cells and T lymphocytes isolated from patients with RA. The <i>PARP9</i> gene exerted significant effects on Jurkat cells (eg, cell cycle, cell proliferation, cell activation and expression of inflammatory factor IL-2). This multistage study identified an interferon-inducible gene interaction network associated with RA and highlighted the importance of <i>PARP9</i> gene in RA pathogenesis. The results enhanced our understanding of the important role of DNA methylation in pathology of RA.