The mediation of circulating inflammatory proteins in the causal pathway from immune cells to osteoarthritis.

BACKGROUND: Observational studies have found that immune cells and circulating inflammatory proteins play a dual role in the progression of osteoarthritis, but the exact mechanism remains unclear. Therefore, this study aimed to investigate whether the causal relationship between immune cells and Knee OA is mediated by circulating inflammatory proteins. METHOD: A two-sample Mendelian Randomization analysis was conducted involving 731 immune cells, 91 inflammatory proteins and OA, utilising summary-level data from genome-wide association studies. The causal relationships between immune cells, inflammatory proteins and OA were sequentially analysed by multivariate Mendelian Randomization and validated using Bayesian weighted Mendelian Randomization. Subsequently, sensitivity analyses were conducted, employing Cochran's Q test to assess heterogeneity, MR-Egger tests to assess pleiotropy, and Steiger directionality tests to rule out reverse causality. Lastly, a two-step approach was employed to ascertain the proportion of inflammatory proteins that mediate immune cell-mediated effects in OA. RESULT: By integrating the inverse variance weighting method with the Bayesian weighting algorithm and conducting sensitivity analyses to exclude unstable factors, we identified 33 immune cell types with significant causal associations with OA (16 with a positive causal effect and 17 with a negative causal effect), as well as six inflammatory proteins (three promoting OA and three protective against OA). Further two-step analysis revealed that these six inflammatory proteins mediated the effects of nine immune cell phenotypes on OA. Among them, TRAIL exhibited the highest mediation proportion (10.99%) in the pro-OA effect of CD25 + IgD + CD24 + B cells and mediated 7.13% of the protective effect of CD16 - CD56 + NKT cells against OA. CONCLUDE: This study provides a comprehensive investigation of the causal relationships between immune cells and Knee OA, and estimates the mediating role of circulating inflammatory proteins. These findings contribute to identifying high-risk populations for OA and offer new insights for early prevention and clinical intervention.