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Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease.

ABSTRACT: Little is known regarding the mechanisms underlying the loss of tolerance in the early and preclinical stages of autoimmune diseases. The aim of this work was to identify the transcriptional profile and signaling pathways associated to non-treated early rheumatoid arthritis (RA) and subjects at high risk. Several biomarker candidates for early RA are proposed.Whole blood total RNA was obtained from non-treated early RA patients with <1 year of evolution as well as from healthy first-degree relatives of patients with RA (FDR) classified as ACCP+ and ACCP- according to their antibodies serum levels against cyclic citrullinated peptides. Complementary RNA (cRNA) was synthetized and hybridized to high-density microarrays. Data was analyzed in Genespring Software and functional categories were assigned to a specific transcriptome identified in subjects with RA and FDR ACCP positive. Specific signaling pathways for genes associated to RA were identified. Gene expression was evaluated by qPCR. Receiver operating characteristic (ROC) analysis was used to evaluate these genes as biomarkers.A characteristic transcriptome of 551 induced genes and 4,402 repressed genes were identified in early RA patients. Bioinformatics analysis of the data identified a specific transcriptome in RA patients. Moreover, some overlapped transcriptional profiles between patients with RA and ACCP+ were identified, suggesting an up-regulated distinctive transcriptome from the preclinical stages up to progression to an early RA state. A total of 203 pathways have up-regulated genes that are shared between RA and ACCP+. Some of these genes show potential to be used as progression biomarkers for early RA with area under the curve of ROC > 0.92. These genes come from several functional categories associated to inflammation, Wnt signaling and type I interferon pathways.The presence of a specific transcriptome in whole blood of RA patients suggests the activation of a specific inflammatory transcriptional signature in early RA development. The set of overexpressed genes in early RA patients that are shared with ACCP+ subjects but not with ACCP- subjects, can represent a transcriptional signature involved with the transition of a preclinical to a clinical RA stage. Some of these particular up-regulated and down-regulated genes are related to inflammatory processes and could be considered as biomarker candidates for disease progression in subjects at risk to develop RA.

SUBMITTER: Macias-Segura N

PROVIDER: S-EPMC5870959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveIt has been suggested that rheumatoid arthritis (RA) may originate at the oral mucosa. The aim of the present study was to assess the oral microbiome and periodontal condition in patients with early RA and individuals at risk of developing RA compared to healthy controls.MethodsThree groups were recruited (n = 50 participants per group): 1) patients with early RA (meeting the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 classification criteria), 2) individuals at risk of developing RA (those with arthralgia who were positive for RA-associated autoantibodies), and 3) healthy controls. A periodontal examination was conducted to assess the presence of bleeding on probing (BOP), pocket probing depth (PPD), and periodontal inflamed surface area (PISA). The microbial composition of subgingival dental plaque, saliva, and tongue coating was assessed using 16S ribosomal DNA amplicon sequencing, and findings were compared between groups with permutational multivariate analysis of variance (PERMANOVA).ResultsThere were no significant differences in any of the 3 periodontal variables between patients with early RA, at-risk individuals, and healthy controls (P = 0.70 for BOP, P = 0.30 for PPD, and P = 0.57 for PISA, by Kruskal-Wallis test). PERMANOVA analyses comparing microbial composition between the groups showed significant differences in the microbial composition of saliva (F = 2.08, P = 0.0002) and tongue coating (F = 2.04, P = 0.008), but not subgingival dental plaque (F = 0.948, P = 0.51). However, in post hoc tests, no significant differences in microbial composition of the saliva or tongue coating were observed between the early RA group and the at-risk group (F = 1.12, P = 0.28 for saliva; F = 0.834, P = 0.59 for tongue coating). In assessing microbial diversity based on the number of zero-radius operational taxonomic units per sample, Prevotella in the saliva and Veillonella in the saliva and tongue coating were each found at a higher relative abundance in samples from patients with early RA and at-risk individuals compared to healthy controls.ConclusionThe results show similarities in the oral microbiome between patients with early RA and at-risk individuals, since in both groups, the oral microbiome was characterized by an increased relative abundance of potentially proinflammatory species when compared to that in healthy controls. These findings suggest a possible association between the oral microbiome and the onset of RA.

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Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease.

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