Severe sepsis and genetic predisposition: systematic review

Severe sepsis remains one of the most lethal outcomes of infection. Beyond clinical and environmental factors, studies have identified genetic variants as important factors, that may impact individual response to severe sepsis. This systematic review aims to synthesize the recent studies on genetic polymorphisms associated with severe sepsis. In accordance with PRISMA guidelines, we conducted a systematic review of the literature (PubMed, 2020–2025) to identify studies investigating genetic predisposition to sepsis. Among the 152 articles examined, 43 satisfied the inclusion criteria. Data regarding populations, genes, polymorphisms, and effect sizes were extracted and analyzed. Most of the studies included in our review focused on genetic susceptibility to sepsis rather than mortality and severity. Genetic polymorphisms in cytokine genes (IL6, TNF, IL10), innate immunity (TLR2, TLR4, P2RX7), complement (MBL2, C4A/C4B), and endothelial regulators (MMP9, THBD) have been linked to a higher risk of sepsis. Other variants such as TGF- β1 − 509 C and P2RX7 - rs17525809, were associated with a lower sepsis risk. Pediatric cohorts consistently displayed lower odds ratio in compared to adults. Most cohorts originate from Europe and East Asia, with a marked underrepresentation of African and Latin American populations. Current data support the role of genetic variations in immune and endothelial pathways in modulating the response to sepsis. However, these data remain insufficient for reliable prediction of sepsis severity and mortality. The fact that studies are focused on specific regions and ethnic groups, which limits the applicability of these findings. At present, genetic profiling for sepsis cannot be recommended for severe sepsis risk stratification or in clinical decision-making. Clinical application requires multi-ethnic, rigorous phenotyping and standardized reporting of severity, mortality and severe sepsis outcomes.