Lactate-related diagnostic signature in rheumatoid arthritis: WGCNA and LASSO analysis with experimental validation

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease. Accumulating evidence reveals that lactate plays a vital role in progression of RA. This study aimed to identify lactate-related genes (LRGs) associated with RA and investigate their potential pathological correlation with immune-infiltrating cells and their potential as diagnostic markers in RA.

We downloaded four RA-related datasets containing 51 RA and 36 healthy synovium samples from the Gene Expression Omnibus (GEO) database and extracted the expression profiles of lactate-related genes to identify differentially expressed genes (DEGs). Subsequently, weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) were employed to identify the hub genes for RA diagnosis. Receiver operating characteristic (ROC) curves were used to validate the specificity and sensitivity of the hub genes. Additionally, we analyzed the infiltration levels of 28 immune cells in the expression profiles and their relationship with the hub genes using single-sample gene set enrichment analysis. Finally, the expression levels and function of hub genes were verified.

We identified 373 differentially expressed LRGs (232 upregulated and 141 downregulated genes) between RA and healthy controls. WGCNA and LASSO analysis results identified TPK1 and IBA57 as potential diagnostic biomarkers for RA. The combination of the two hub genes showed great diagnostic ability (AUC > 0.8) in multiple independent validation dataset. Additionally, IBA57 may involved in the immune mechanism of DC cells, whereas TPK1 may be involved in regulating macrophage function in the immune response to RA. Also, TPK1 is highly expressed in RA, and knockdown TPK1 attenuated RA-FLS invasion and migration.

These data indicate that lactate-related gene TPK1 and IBA57 are valuable diagnostic biomarkers for RA and are closely associated with immune cell infiltration, and TPK1 may play an important role in RA progression. These findings provide new insights into the pathogenesis of RA and potential diagnostic targets.