What question did this study set out to answer?

This study aims to evaluate the impact of the IL-18 rs187238 polymorphism on sepsis prognosis and inflammatory response.

June 6, 2026Open Access

Genetic variation at the IL-18–137C>G is associated with poor sepsis prognosis and enhanced inflammatory responses: a multicenter hospital-based study

ZLZhuoji LiSecond Affiliated Hospital of Guangzhou Medical University WGWanjie GuFirst Affiliated Hospital of Jinan University LLLizhen LiuGuangdong Medical College

Key Points

This study aims to evaluate the impact of the IL-18 rs187238 polymorphism on sepsis prognosis and inflammatory response.
Conducted a multicenter case-control study with 784 sepsis patients and 776 healthy controls.
Genotyped IL-18 rs187238 polymorphism using imLDR™ multiplex SNP genotyping method.
Performed ELISA and qRT-PCR for inflammatory cytokine expression and functional analysis through dual-luciferase assays.
The CG/GG genotypes were associated with higher 28-day ICU mortality (OR = 1.470, 95% CI = 1.029–2.129, P = 0.037).
Sepsis patients with CG/GG genotypes showed significantly higher IL-18 levels and increased expression of IL-1β, IL-6, and ICAM-1.
Dual-luciferase assays confirmed that the G allele enhances IL-18 promoter activity.

Abstract

Background Sepsis is a life-threatening condition caused by dysregulated immune responses, leading to inflammation, tissue damage, and organ failure. This study investigates the role of the IL-18 rs187238 (−137CG) polymorphism in sepsis susceptibility, progression, and patient prognosis. Methods A multicenter case-control study was conducted with 784 sepsis patients and 776 healthy controls. The IL-18 rs187238 polymorphism was genotyped using imLDR™ multiplex SNP genotyping method. ELISA and qRT-PCR were used to detect related inflammatory cytokine expression, while functional analysis was performed using dual-luciferase assays to evaluate the impact of the rs187238 variant on IL-18 promoter activity. Results We observed a significant association between the rs187238 polymorphism and 28-day ICU mortality in sepsis patients. The CG/GG genotypes (OR = 1.470, 95% CI = 1.029–2.129, P = 0.037) were more frequently observed in non-survivors compared to survivors, with a notable difference in the frequency of the G allele (OR = 1.534, 95% CI = 1.111–2.133, P = 0.010). Kaplan-Meier survival analysis confirmed that patients with CG/GG genotypes had significantly lower 28-day survival rates compared to those with the CC genotype ( P = 0.028). However, no significant differences in genotype and allele frequencies were observed between cases and healthy controls, nor between sepsis and septic shock patients. Sepsis patients with CG/GG genotypes had significantly higher IL-18 levels than those with the CC genotype. Dual-luciferase assays confirmed that the G allele increased IL-18 promoter activity, supporting its genetic influence on IL-18 expression. Additionally, sepsis patients with CG/GG genotypes expressed significantly increased levels of IL-1β, IL-6, and ICAM-1 than those with CC genotype. IL-18 treatment enhanced the expression of IL-1β, IL-6, IL-27, TNF-α, and MCP-1 in THP-1 macrophages upon LPS stimulation. In HUVECs, IL-18 treatment further enhanced LPS-induced IL-6, IL-27, TNF-α, and ICAM-1 expression, while promoting apoptosis and reducing VE-cadherin levels, emphasizing its role in inflammation and endothelial dysfunction in sepsis. Conclusion The IL-18 rs187238 CG polymorphism is linked to higher IL-18 expression and intensified inflammatory responses, which are associated with poor sepsis prognosis. The sepsis-associated risk rs187238-G allele serves as a potential prognostic biomarker for sepsis-related mortality. Targeting IL-18 or its genetic variations might offer new avenues for sepsis therapy.

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