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

Abstract

BackgroundLittle 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.MethodsWhole 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.ResultsA 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.ConclusionThe 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.

Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

“…These are conditions in which elevated IL-1 and IL-6 activity are considered to play a key role in disease pathogenesis, evidenced by clinical improvement following therapeutic antagonism of these cytokines (22)(23)(24)(25). The blood transcriptome of untreated JIA patients displayed elevated IL-1 and IL-6 bioactivity (fig 2A) (26), but this was not consistently evident in several RA blood transcriptome datasets (fig S1) (27)(28)(29).…”

Current status of use of high throughput nucleotide sequencing in rheumatology

“…High throughput gene expression profiling using DNA microarrays have already provided unprecedented views into the blood transcriptome of, for example, SLE, 67 68 RA, 69 SpA, 70 and thus paved the way for the development of personalised diagnostic and therapeutic strategies.…”

Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis

“…Currently, transcriptomic and microarray analyses have been widely used in a variety of diseases, including RA, to identify new biomarkers to improve diagnosis and treatment [8][9][10]. In addition, competitive endogenous RNA (ceRNA) networks can elucidate a new mechanism for promoting the development of the disease in a transcriptional regulatory network [11].…”