Human Genetic Analysis Reveals Circulating Alpha-1 Antitrypsin Level as a Protective Factor in Sepsis.

Area of Science:

• Genetics
• Proteomics
• Infectious Diseases

Background:

• Sepsis is a major global health threat with high mortality.
• Current targeted therapies for sepsis are limited.
• Identifying novel therapeutic targets is crucial.

Purpose of the Study:

• To identify novel therapeutic targets for sepsis using a proteogenomic approach.
• To investigate the causal role of alpha-1 antitrypsin (AAT) in sepsis.
• To explore SERPINA1 as a potential drug repurposing candidate.

Main Methods:

• Meta-analysis of genome-wide association studies (GWAS) in sepsis cases and controls.
• Mendelian randomization (MR) and colocalization analyses.
• Proteomic profiling in independent sepsis cohorts.

Main Results:

• Identified four genome-wide significant loci associated with sepsis, including a variant in SERPINA1.
• Demonstrated a causal and protective effect of higher genetically predicted AAT levels on sepsis risk.
• Observed attenuated AAT levels in variant carriers during acute illness, indicating impaired protease-antiprotease balance.

Conclusions:

• Provides the first human genetic evidence for AAT's causal role in sepsis.
• Positions SERPINA1 (encoding AAT) as a high-priority target for sepsis drug repurposing and therapy.
• Supports therapeutic modulation of the AAT pathway for sepsis treatment.