Genetic evidence for CTSH as a potential therapeutic target in sepsis

This study aimed to systematically evaluate the potential causal relationship between plasma and cerebrospinal fluid protein levels and sepsis risk through the integration of Mendelian randomization (MR) analysis, external validation, and Bayesian colocalization analysis. It further sought to explore the genetic mechanisms of key proteins and their potential as drug targets. We performed two-sample MR to screen plasma and cerebrospinal fluid proteins for genetic associations with sepsis. The main findings were then evaluated using independent datasets for external validation and assessed for shared causal variants with sepsis using Bayesian colocalization. Network and drug-database analyses were conducted as exploratory functional annotations. The MR analysis initially identified 3 key proteins - CTSH, IL6R, and OLFM1 - with higher genetically predicted CTSH levels associated with increased sepsis risk, supported by external validation (Primary: odds ratio = 1.10, 95% confidence interval = 1.03-1.17, P = .004; SameVariant: odds ratio = 1.07, 95% confidence interval = 1.02-1.13, P = .004). Colocalization analysis indicated that the genetic correlation between CTSH and sepsis was relatively low (PP.H4.abf = .0585). The protein-protein interaction network revealed that CTSH is closely linked to various immune-related genes. Genomics of Drug Sensitivity in Cancer database analysis suggested that CTSH may be targeted by existing drugs, indicating its potential for drug intervention. CTSH shows a consistent genetic association with sepsis risk, but colocalization provides only weak evidence for a shared causal variant, so the overall genetic support is modest. Further functional and clinical validation is needed before considering CTSH for therapeutic translation.