Abstract
BackgroundEpigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA). To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).MethodsTotal RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12). Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.ResultsWhole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs. Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups. Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart. We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs. Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks. Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.ConclusionsWe highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA. Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.
Highlights
Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA)
Whole blood miRNA expression profile was altered in patients with RA and First-degree relative (FDR) Using targeted TaqMan® miRNA assay probes (Life Technologies), we analyzed the expression of 33 selected miRNAs
Our analysis indicated that RA and FDR groups exhibited uniquely similar miRNA expression patterns compared with Healthy control subjects (HC) in whole blood samples (Table 2 and Fig. 1; Additional file 1: Table S4), but there were notable differences between these three groups
Summary
Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA). In studying the first-degree relatives (FDRs) of INA patients with RA, we have demonstrated frequent RF and ACPA seropositivity, and we have shown that the serum cytokine profile of the FDRs resembles that of their affected relatives more so than that of control subjects with no family history of autoimmune disease [6,7,8]. This population is ideally suited for studying the onset of RA in high-risk individuals and the potential role that genetic, environmental, and epigenetic factors play in the process
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