Characterising sex differences in rheumatoid arthritis: a systematic review and meta-analysis of transcriptomic studies

Previous studies have described sex-based differences in the epidemiological and clinical features of autoimmune diseases, including rheumatoid arthritis (RA). In this regard , it is known that the immune system acts differently between men and women, and that sex hormones play a key role in such disparities . How ever, the differences in the mo lecular mechanisms are not fully understood. Thus, a better under standing of these mechanisms could pro vide greater diag nostic precision and personalised treatments by sex. Therefore, the aim of this study was to identify and understand the molecular mechanisms underlying sex-based differences in rheumatoid arthritis. This goal was achieved in three steps. First, we conducted a systematic review of rheumatoid arthritis studies with gene expression microarray or RNA-seq data from healthy individuals and patients. Second, the selected studies were individually analysed. This step included an exploratory analysis, a differential expression analysis, and a functional enrichment analysis of biological processes from the Gene Ontology (GO) and KEGG pathways. Finally, we performed a gene meta-analysis using a random effects model, followed by a functional enrichment of the overall results. As a result, five datasets that included 570 samples were retrieved from the Gene Expression Omnibus (GEO) repository. After the meta-analysis, 10 genes, 90 biological processes and 11 KEGG pathways were identified as significantly sex-dependent. In addition, the results were synthesized using the REVIGO tool and GO slim terms. Among other functions, the outcomes from the enrichment suggest an increased activity of the immune system and a greater presence of energy precursors in female RA patients. Male RA patients, instead, showed an overrepresentation of terms related to protein biosynthesis and negative regulation of osteoblasts. Our findings could lead to the discovery of new therapeutic targets and be the basis of future research devoted to sex-specific precision medicine in ...