BIRC6 modifies risk of invasive bacterial infection in Kenyan children

Area of Science:

• Genetics
• Infectious Diseases
• Pediatrics

Background:

• Invasive bacterial disease is a significant cause of illness and death in African children.
• Clinical presentation of sepsis is often indistinguishable across different bacterial pathogens.
• Existing genetic susceptibility loci are largely pathogen-specific, suggesting a lack of understanding of shared genetic factors in bacterial sepsis.

Purpose of the Study:

• To identify children with a high probability of invasive bacterial disease among critically ill Kenyan children with Plasmodium falciparum parasitemia.
• To perform a cross-trait genome-wide association study to uncover shared genetic architecture for invasive bacterial infections.
• To identify novel genetic risk loci associated with invasive bacterial disease independent of malaria risk.

Main Methods:

• Utilized probabilistic diagnostic models to identify children with invasive bacterial disease.
• Constructed a joint dataset of 1445 bacteremia cases, 1143 severe malaria cases, and population controls from genotyped critically ill Kenyan children.
• Conducted a cross-trait genome-wide association study, weighting cases by their probability of bacterial disease.

Main Results:

• Identified and validated a novel genetic risk locus for invasive infection caused by multiple bacterial pathogens.
• The identified locus showed no apparent effect on malaria risk.
• The locus was found to modify splicing of the BIRC6 gene in stimulated monocytes.

Conclusions:

• The study implicates BIRC6 gene regulation, specifically apoptosis and autophagy pathways, in the pathogenesis of sepsis in Kenyan children.
• A shared genetic architecture for invasive bacterial sepsis, independent of malaria, has been identified.
• This discovery provides new targets for understanding and potentially treating invasive bacterial diseases in vulnerable populations.