A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression

Area of Science:

• Genetics and Molecular Biology
• Immunology and Infectious Diseases
• Critical Care Medicine

Background:

• Single nucleotide polymorphisms (SNPs) are increasingly recognized for their role in sepsis susceptibility and pathogenesis.
• Preliminary studies suggested a link between ADAM10 genetic polymorphism and sepsis development, but the underlying mechanisms remain unclear.
• Sepsis, a life-threatening organ dysfunction, has high mortality rates, necessitating the identification of genetic factors and therapeutic targets.

Purpose of the Study:

• To confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and sepsis progression.
• To elucidate the molecular mechanism by which this SNP influences sepsis pathogenesis.
• To investigate the role of the EGR1/ADAM10 pathway in sepsis-related inflammation and outcomes.

Main Methods:

• A multi-center, large-scale case-control association study was conducted to analyze the rs653765 G→A polymorphism in sepsis patients.
• In vitro studies utilized reporter assays to assess the functional impact of the SNP on ADAM10 promoter activity and transcription factor binding.
• Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays were employed to confirm direct interactions.
• In vivo experiments in a mouse endotoxemia model were performed to evaluate the therapeutic potential of EGR1 intervention.

Main Results:

• The rs653765 G→A polymorphism was found to be positively correlated with sepsis development.
• EGR1 (Early Growth Response 1) transcription factor binding to the ADAM10 promoter was altered by the SNP, affecting ADAM10 gene expression.
• The EGR1/ADAM10 pathway was identified as crucial for regulating inflammatory responses in sepsis.
• In vivo EGR1 intervention reduced pro-inflammatory cytokine secretion and improved survival in a mouse model of endotoxemia.

Conclusions:

• The ADAM10 promoter rs653765 G→A polymorphism is a significant genetic factor associated with sepsis progression.
• This SNP modulates the EGR1/ADAM10 pathway, impacting sepsis severity and inflammatory responses.
• The findings provide novel insights into sepsis pathogenesis and identify the EGR1/ADAM10 pathway as a potential therapeutic target for sepsis and other inflammatory diseases.