CLP1 is a Prognosis-Related Biomarker and Correlates With Immune Infiltrates in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, heterogeneous autoimmune disease with a high disability rate that seriously affects society and individuals. However, there is a lack of effective and reliable diagnostic markers and therapeutic targets. In this study, we identified diagnostic markers of RA based on RNA modification and explored its role as well as degree of immune cell infiltration. We used the gene expression profile data of three synovial tissues (GSE55235, GSE55457, GSE77298) from the Gene Expression Omnibus (GEO) database and the gene of 5 RNA modification genes (including m6A, m1A, m5C, APA, A-1), combined with cluster analysis, identified four RNA modifiers closely related to RA (YTHDC1, LRPPRC, NOP2, and CLP1) and five immune cells namely T cell CD8, CD4 memory resting, T cells regulatory (Tregs) Macrophages M0, and Neutrophils. Based on the LASSO regression algorithm, hub genes and immune cell prediction models were established respectively in RA and a nomogram based on the immune cell model was built. Around 4 key RNA modification regulator genes, miRNA-mRNA, mRNA-TF networks have been established, and GSEA-GO, KEGG-GSEA enrichment analysis has been carried out. Finally, CLP1 was established as an effective RA diagnostic marker, and was highly positively correlated with T cells follicular helper (Tfh) infiltration. On the other hand, highly negatively correlated with the expression of mast cells. In short, CLP1 may play a non-negligible role in the onset and development of RA by altering immune cell infiltration, and it is predicted to represent a novel target for RA clinical diagnosis and therapy.

Recent advances of m6A methylation in skeletal system disease

“…Given that dysregulation of m6A modifications plays a crucial role in: (1) Affecting ECM degradation, immune microenvironment and apoptosis in OA chondrocyte; (2) Regulating inflammatory response of immunocytes, and rheumatoid fibroblast-like synoviocytes proliferation, migration and invasion; (3) Maintaining bone homoeostasis of OP, including osteoblasts, osteoclasts and BMSCs; (4) Proliferation, and metastasis of OS [ 108 , 209 ]. It is believable that m6A modifications can offer novel ideas for early diagnosis, clinical therapy and prognosis of skeletal system diseases [ 210 ]. For example, Luo et al firstly revealed that the expression of ALKBH5, FTO, and YTHDF2 in peripheral blood of RA patients were significant low compared to control patients [ 211 ].…”

Mast Cell Involvement in the Pathogenesis of Selected Musculoskeletal Diseases

“…The list of contradictions is extensive. For example, degranulated MCs are associated with RA severity, but some studies claim that mRNA levels of MC-specific genes are inversely associated with disease severity [ 52 ]. MCs also revealed a significant negative correlation with CLP1, an effective RA diagnostic marker.…”

Expression patterns of eight RNA-modified regulators correlating with immune infiltrates during the progression of osteoarthritis

“…We downloaded the GSE51588 dataset containing 30 OA and 10 normal sub-chondral samples from the Gene Expression Omnibus database (GEO, https://www.ncbi.nlm.nih.gov/geo/). Our study selected nine types of RNA regulators that have been widely analyzed (14,18,19). The nine gene sets of 109 RNA modification regulators were previously identified by Mao et al (14) and Chen et al (19), and are listed in Table S1.…”

“…Up to now, more than 170 types of RNA modifications have been detected in eukaryotes; many of these have been shown to be strongly related to various diseases ( 17 ). N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytidine (5mC), 7-methylguanosine (m7G), alternative polyadenylation (APA), 2′-O- methylation (Nm), uridine-to-pseudouridine (Ψ), adenosine-to-inosine transition (A-to-I), and 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) have all been commonly investigated over recent years for their respective roles in the progression of disease ( 14 , 18 – 20 ). Previous research found that targeted inhibition of m6A regulator—METTL3 could attenuate the senescence of synovial fibroblasts and limit OA progression ( 21 ).…”