Genome-wide association study of pediatric bacteremia and sepsis

BackgroundSepsis is defined as a dysregulated host response to infection leading to organ dysfunction. It represents a major global health concern, particularly in childhood. The precise underlying pathophysiological mechanisms remain poorly understood. MethodsUsing samples and clinical data from 650 children enrolled in the Swiss Pediatric Sepsis Study, a national multicenter cohort study for culture-proven bacterial sepsis, and from 1395 controls, we explored the human genetic determinants of inter-individual variability in sepsis-related outcomes. We used a case-control study design to search for associations between genome-wide polymorphisms and susceptibility to sepsis, and case-only analysis for specific characteristics of the disease. FindingsWe identified one locus significantly associated with sepsis susceptibility, encompassing the CTNNAL1 and ELP1 genes. InterpretationOur results suggest a genetic modulator of sepsis susceptibility in children. FundingThis study was funded by grants from the Swiss National Science Foundation (320030_201060 and 342730 153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSBlood culture-confirmed bacterial sepsis in children remains an important cause of morbidity and mortality. Several prospective studies from the Swiss Pediatric Sepsis Study (SPSS) have defined its incidence, clinical features, and outcomes in Switzerland. A 2017 nationwide cohort study reported an incidence of 25.1 per 100,000 children annually and a 30-day mortality rate of 7%, with risk of death closely associated with the presence and number of organ dysfunctions. A neonatal-focused analysis identified three distinct clinical subgroups (early-onset, hospital-acquired, and community-acquired late-onset sepsis), each with specific pathogens, risk profiles, and outcomes. Hospital-acquired infections were most frequent and carried the highest case fatality. In a separate cohort of previously healthy children with community-acquired sepsis, rare variants in primary immunodeficiency genes were identified in 20% of cases, although most were of uncertain significance. Another SPSS study assessed organ dysfunction scores in paediatric sepsis and found similar performance in predicting 30-day mortality. Cardiovascular, respiratory, and neurologic dysfunctions were most strongly associated with death, suggesting that simplified assessment may be feasible. Added value of this studyThis is the first genome-wide association study of paediatric bacterial sepsis based on a national cohort with blood culture-confirmed diagnoses. The cohort included 650 sepsis cases and 1395 population-based controls. A genome-wide significant susceptibility locus was identified on chromosome 9 (CTNNAL1/ELP1). Some biological relevance of this locus has previously been demonstrated independently. The study expands previous SPSS research by integrating epidemiological data with genome-wide genetics and by applying stringent ancestry correction and imputation within the clinical phenotype. The findings offer new avenues for investigating genetic contributions to paediatric sepsis susceptibility. Implications of all the available evidenceCombined with earlier SPSS studies, these findings support a model in which both genetic and clinical factors contribute to sepsis susceptibility and outcome in children. The identification of a susceptibility locus near CTNNAL1 and ELP1 provides a new basis for mechanistic studies and implicates transcriptional regulation and NF-{kappa}B signalling pathways. Use of a microbiologically confirmed phenotype enhances interpretability and relevance for translational research. These results provide a foundation for future work on host-pathogen interactions, genetic risk stratification, and targeted interventions in paediatric sepsis.