Molecular crosstalk and potential causal mechanisms of rheumatoid arthritis and sarcopenia co-morbidity: A gene integration analysis

INTRODUCTION: Rheumatoid arthritis (RA) promotes the onset and progression of sarcopenia, yet mechanisms of co-morbidity between RA and sarcopenia are under-explored. Therefore, this study integrated Gene Expression Omnibus (GEO) and Genome-wide association studies (GWAS) data to comprehensively identify shared genes, associated mechanisms, and biological pathways in RA and sarcopenia. METHODS: Utilizing two GEO datasets-GSE226151, which includes 60 RNA-seq samples of skeletal muscle from healthy aged, pre-sarcopenia, and sarcopenia individuals, and GSE55235, with 20 RNA-seq samples of synovial tissue from healthy and RA joints-we performed differentially expressed genes analysis, weighted gene co-expression network analysis to identify crosstalk genes in RA and sarcopenia, and enrichment analysis for these genes. Using relevant GWAS datasets, SMR analyses and cis-eQTL analyses were performed. We further validated and identified key crosstalk genes and explored potential causal associations between key crosstalk genes and RA and sarcopenia-related traits. RESULTS: We identified 25 crosstalk genes shared between RA and sarcopenia, which are involved in immune-inflammatory response pathways, including neutrophil extracellular trap formation and Fc gamma receptor-mediated phagocytosis. SMR analysis further identified six core crosstalk genes: NCF1, FCGR2A, FCGR3A, SORL1, FCGR3B, and ITGAX (PSMR < 0.05). cis-eQTL analysis showed that FCGR2A might have a negative causal association with appendicular lean mass, whole body fat-free mass, and a positive causal association with RA (P < 0.05). CONCLUSION: Overall, this study is the first to reveal the molecular crosstalk between RA and sarcopenia, identifying 25 shared genes and key immune-inflammatory response-related pathways. Further SMR and cis-eQTL analyses were conducted to validate six core genes, with FCGR2A emerging as a potential drug target for RA-associated sarcopenia. These findings provide new insights into the comorbid mechanisms of RA and sarcopenia, offering potential therapeutic targets for both conditions.