Mendelian Randomization and Transcriptome Analyses Reveal Important Roles for CEBPB and CX3CR1 in Osteoarthritis

<b>Background</b>: Chemokines play a pivotal role in the progression of osteoarthritis (OA), but their exact mechanisms remain unclear. This study aimed to identify potential chemokine-associated biomarkers and investigate their causal relationships with OA. <b>Methods</b>: Transcriptome and genome-wide association study (GWAS) data were obtained from public databases, while chemokine-related genes (CRGs) were sourced from the literature. Initially, CRGs were expanded, followed by Mendelian randomization (MR) analysis, differential expression analysis, machine learning, and receiver operating characteristic (ROC) curve plotting to identify potential biomarkers. The causal relationships between these biomarkers and OA, as well as their biological functions, were further explored. <b>Results</b>: Fourteen candidate genes were identified for machine learning analysis, with <i>DDIT3</i>, C<i>E</i>BPB, <i>CX3CR1</i>, and <i>ARHGAP25</i> emerging as feature genes. <i>CEBPB</i> and <i>CX3CR1</i>, which exhibited AUCs > 0.7 in the GSE55235 and GSE55457 datasets, were selected as potential biomarkers. Notably, <i>CEBPB</i> expression was lower, while <i>CX3CR1</i> expression was elevated in the case group. Furthermore, both genes were co-enriched in spliceosome, lysosome, and cell adhesion molecule pathways. MR analysis confirmed that <i>CEBPB</i> and <i>CX3CR1</i> were causally linked to OA and acted as protective factors (IVW model for <i>CEBPB</i>: OR = 0.9051, <i>p</i> = 0.0001; IVW model for <i>CX3CR1</i>: OR = 0.8141, <i>p</i> = 0.0282). <b>Conclusions</b>: <i>CEBPB</i> and <i>CX3CR1</i> were identified as potential chemokine-related biomarkers, offering insights into OA and suggesting new avenues for further investigation.