Genetic Variation in the Alternative Complement Pathway Contributes to Individual Susceptibility to Bacteremia and...

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• The alternative complement pathway is crucial for fighting infections like bacteremia.
• Dysregulation of this pathway can worsen inflammation and outcomes in sepsis.

Purpose of the Study:

• To identify genetic variants in alternative pathway (AP) genes linked to bacteremia and sepsis risk.

Main Methods:

• Utilized summary statistics from a large-scale genome-wide by phenome-wide association study (MVP) of over 600,000 individuals.
• Analyzed associations between single-nucleotide polymorphisms (SNPs) in AP genes and sepsis/bacteremia Phecodes.
• Investigated regulatory SNPs using eQTL data and in silico modeling.

Main Results:

• Identified 25 lead genic SNPs associated with sepsis/bacteremia incidence (minor allele frequency >1%).
• Found significant associations in complement factor B (CFB), complement factor I (CFI), and C5a receptors (C5AR1/C5AR2).
• Discovered regulatory SNPs impacting AP gene expression, particularly near CFB, CFD, and C5AR1.

Conclusions:

• Identified potentially clinically relevant genetic variations in the alternative complement pathway.
• These variations may influence individual susceptibility to bacteremia and sepsis.
• Further research is needed to elucidate mechanisms and clinical implications.