Causal effects between mitochondrial functional proteins and sepsis: A Mendelian randomization study

More and more studies have shown that mitochondria play a key role in the pathogenesis of sepsis. However, the pathogenesis of sepsis is complex, and there are ethical and implementation challenges in conducting large-scale randomized controlled trials. Mendelian randomization (MR) analysis selects genetic variants as instrumental variables based on genome-wide association studies (GWAS) to infer causal relationships, which can avoid traditional confounding factors. The data of this study were sourced from the IEU OpenGWAS database. The GWAS summary data of 66 mitochondrial functional proteins (MPs) and 5 types of sepsis and their subtypes were included. The "TwoSampleMR" R package was used for analysis. Five methods, including the inverse variance weighted (IVW) method, were used for causal effect analysis. Horizontal pleiotropy and heterogeneity were detected, and sensitivity and reverse association analyses were carried out. The results showed that MICU3, GRPEL1, HTRA2, ISCU, NDUFS4, MCEE, ES1, and LONP1 were protective factors for sepsis, while Grx2, MRM3, and PheRS were risk factors. Among them, MICU3 was strongly correlated with sepsis (28-day death in ICU), and Grx2 was strongly correlated with sepsis (28-day death). This study used 5 MR analysis methods to explore the causal relationships between 66 MPs and 5 types of sepsis and their subtypes for the first time. It was found that some MPs were potential protective factors for sepsis or its subtypes, while some were risk factors. These risk factor MPs may have time-dependent bidirectional effects in the regulation of mitochondrial function in sepsis. This study provides new evidence for elucidating the role of these MPs in the pathophysiology of sepsis, which helps to gain an in-depth understanding of the pathogenesis of sepsis and also lays the foundation for exploring future treatment strategies.