The Relationship between Cathepsins and Sepsis: A Mendelian Randomization Study

Abstract

Background An increasing body of evidence suggests a connection between cathepsins and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between cathepsins and sepsis, we conducted multiple Mendelian randomization (MR) analyses. Methods In this study, MR analysis was employed to investigate the causal associations between nine cathepsins and various severities of sepsis (sepsis, 28-day death, under 75). The research design consisted of forward MR analysis, reverse MR analysis and multivariable MR analysis. Under the premise of meeting the three fundamental assumptions of MR studies, genetic instrumental variables (IVs) were selected for specific analyses. The MR studies utilized the inverse variance-weighted (IVW) method as the primary analytical approach. Results In the forward MR analysis, the IVW method indicated that Cathepsin E and Cathepsin O are identified as potential risk factors for the occurrence of sepsis and sepsis (under 75). Additionally, a negative correlation was observed between Cathepsin F and 28-day mortality. Conversely, results from the reverse MR analysis suggested that the occurrence of sepsis might contribute to a reduction in the levels of Cathepsin Z. Within the multivariable MR analysis, incorporating nine cathepsins as covariates, Cathepsin O emerged as a risk factor for 28-day mortality. Interestingly, the multivariable MR analysis also affirmed that with an elevation in the levels of Cathepsin E, the risk of sepsis (under 75) increases. Conclusion Our MR study, for the first time from a genetic perspective, provides evidence of a causal relationship between cathepsins and the susceptibility to sepsis. This discovery holds significant implications for guiding clinical practices in the treatment of sepsis.