Immunological Insights into the Causal Link Between Arthritis, Osteoarthritis, and Frailty: An Integrated Analytical...

Background: Previous observational studies have observed associations between rheumatoid arthritis (RA), knee osteoarthritis (KOA), hip osteoarthritis (HOA), and frailty, but the causal relationships remain unestablished. Objective: This study aimed to evaluate the causal relationships between RA, KOA, HOA, KneeHipOA, and frailty using Mendelian randomization (MR) and bioinformatics analysis. Methods: We performed two-sample MR to test for causality between RA, KOA, HOA, KneeHipOA, and frailty. Subsequently, we combined our results in a meta-analysis and conducted multiple sensitivity analyses (MR-Egger, weighted median, constrained maximum likelihood and model averaging (cML-MA), and Bayesian weighted MR (BWMR)). We further explored the role of circulating immune cells and the effects of RA and OA-related gene expression on frailty. Results: Genetically determined RA, KOA, HOA, and KneeHipOA were correlated with a higher risk of frailty. The results of multivariate MR analyses were consistent with those of two-sample MR. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis indicated that RA and OA-related genes were primarily enriched in various immune responses. Our findings suggested that increases in monocyte cell AC, eosinophil cell AC, and neutrophil cell AC were associated with a higher risk of frailty. Conclusion: This research provides evidence supporting the associations between RA, KOA, HOA, KneeHipOA, and frailty. It also highlights the significant role of circulating immune cells in the development of frailty, indicating the importance of frailty management from an immunological perspective.