Genetic Factors in Sepsis Susceptibility and Outcomes

Sepsis arises from a dysregulated host response to infection, in which inherited genetic variation exerts a significant influence on individual susceptibility, disease progression and mortality. Both common and rare single-nucleotide polymorphisms (SNPs) within genes governing innate immunity, inflammatory cytokine production and coagulation pathways can modulate the likelihood of developing sepsis, the severity of organ dysfunction and responsiveness to therapy. Genome-wide association studies have uncovered loci associated with 28-day mortality, while analysis of rare deleterious variants suggests that impairments in cell-signalling and immune pathways may paradoxically confer a protective effect against excessive inflammation. Polygenic risk scores combining multiple SNPs show promise in stratifying patients according to prognostic risk. Functional investigations of toll-like receptor variants, cytokine gene polymorphisms and downstream signalling components such as NF-κB, JAK-STAT and MAPK pathways have provided mechanistic insight and highlighted potential therapeutic targets. Integrating genetic profiles with clinical parameters has the potential to inform early risk stratification, guide immunomodulatory therapy and improve outcomes on a global scale.

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Genetic Factors in Sepsis Susceptibility and Outcomes publication trend

The graph below shows the total number of articles in genetic factors in sepsis susceptibility and outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Single-nucleotide polymorphism (SNP): A single base-pair variation in the genome influencing gene function or expression.

Polygenic risk score (PRS): An aggregate measure of genetic susceptibility calculated from multiple weighted SNPs.

Biomarker: A measurable molecule or gene expression pattern indicative of disease state or prognosis.

Innate immunity: The body’s first line of defence against pathogens, involving cells and receptors such as toll-like receptors.

Toll-like receptor (TLR): A family of pattern-recognition receptors that detect microbial components and activate inflammatory signalling.

NF-κB pathway: A key transcriptional regulator of inflammatory and immune responses activated by diverse stimuli.

References

1. Genetic polymorphisms, biomarkers and signaling pathways associated with septic shock: from diagnosis to therapeutic targets. Burns & Trauma (2024).
2. Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis. Frontiers in Immunology (2023).
3. Population-specific genetic-risk scores enable improved prediction of mortality within 28 days of sepsis onset: a retrospective Taiwanese cohort study. Journal of Intensive Care (2025).
4. Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality. EBioMedicine (2016).
5. Host genetic variants in sepsis risk: a field synopsis and meta-analysis. Critical Care (2019).
6. Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive. EBioMedicine (2016).