How does OA affect sepsis? An observational study and Mendelian randomization mediation analysis.

Objective: To investigate the causal relationships among osteoarthritis (OA), sepsis, and potential mediators, which include immune cell phenotypes, metabolic, and inflammation. Methods: Firstly, the observational study extracted data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The exposure was OA and the control group was patients without any diagnosis of OA. The outcome was a diagnosis of sepsis in the ICU. Secondly, we analyzed summary data from genome-wide association studies on OA, 731 immune cell phenotypes, 1400 plasma metabolites, 91 inflammation factors, and sepsis (diagnosis and 28-day survival), with GWAS datasets including up to ∼30 million SNPs for OA phenotypes and ∼12 million SNPs for sepsis-related outcomes. Bidirectional Mendelian Randomization (MR) analysis was conducted to explore the causal links between OA and sepsis. Results: In observational study, the MIMIC-IV study did not observe a significant association between any OA and sepsis (Odds Ratio (OR) = 1.04, 95% CI: 0.87-1.24). Similarly, lower limb OA showed no correlation with sepsis (OR = 1.21, 95% CI: 0.82-1.77). However, a causal effect of hip osteoarthritis on the risk of developing sepsis was identified (OR: 1.09, 95% CI: 1.01-1.18, P = 0.024). Additionally, we found that sphingomyelin levels and X-24585 levels act as mediators in the causal relationship between hip OA and sepsis, with mediation proportions of 12.4% and 14.2%, respectively. Conclusion: No association between OA and sepsis diagnosis was observed in this cross-sectional study, possibly due to confounding. However, with the MR analysis in GWAS data, hip OA emerged as a potential risk factor for sepsis, with metabolic factor likely acting as mediator. Further mechanisms remain unclear.