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

Area of Science:

• Genetics
• Mitochondrial Biology
• Sepsis Pathophysiology

Background:

• Mitochondria play a significant role in sepsis development.
• Large-scale clinical trials for sepsis are challenging.
• Mendelian randomization (MR) offers a method to infer causality, avoiding confounding factors.

Purpose of the Study:

• To investigate the causal relationships between mitochondrial functional proteins (MPs) and sepsis using MR.
• To identify specific MPs that act as protective or risk factors in sepsis pathogenesis.

Main Methods:

• Utilized genome-wide association study (GWAS) summary data for 66 MPs and 5 sepsis types from the IEU OpenGWAS database.
• Employed the "TwoSampleMR" R package and five analysis methods, including inverse variance weighted (IVW).
• Conducted sensitivity analyses to detect and address horizontal pleiotropy and heterogeneity.

Main Results:

• Identified eight MPs (MICU3, GRPEL1, HTRA2, ISCU, NDUFS4, MCEE, ES1, LONP1) as protective factors for sepsis.
• Identified three MPs (Grx2, MRM3, PheRS) as risk factors for sepsis.
• Found strong associations between MICU3 and sepsis (28-day ICU death), and Grx2 and sepsis (28-day death).

Conclusions:

• This study is the first to explore causal links between 66 MPs and sepsis subtypes using MR.
• Several MPs were identified as potential protective or risk factors, highlighting their role in sepsis pathophysiology.
• Findings provide a foundation for understanding sepsis mechanisms and developing future therapeutic strategies.