Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway

Background: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants. Methods: We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses. Results: In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10⁻⁴ in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS. Conclusion: Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk. Impact: Genes associate with late onset neonatal sepsis.Notch pathway genes are overrepresented in associations with sepsis.Genes associating with sepsis do not overlap between males and females.Sexual dimorphism can lead to sex specific treatment of sepsis.