Clinical significance and prognostic value of SIRT1 genetic variants in sepsis: a multicenter hospital-based case-control study.

Abstract

Background: SIRT1 exerts pivotal roles in the pathogenesis of sepsis. However, the clinical relevance of SIRT1 genetic variants in the onset and progression of sepsis remains poorly understood. This multicenter hospital-based case-control study, for the first time, explored the potential genetic association of SIRT1 genetic variants with sepsis, as well as their impact on sepsis-associated inflammation. 785 septic patients and 776 controls from Han Chinese population were enrolled from four large Chinese general hospitals.

Results: SIRT1 rs12778366 T > C (785 cases, 776 controls) and rs4746720 T > C (765 cases, 774 controls) polymorphisms were successfully genotyped. No significant differences in the genotype/allele frequencies of SIRT1 polymorphisms between sepsis and control groups. The frequencies of rs4746720 TC/CC genotypes were significantly lower in patients with septic shock than those with sepsis subtype (OR = 0.685, 95% CI = 0.508-0.924, P = 0.014), while the TT genotype and T allele were significantly more frequent in mortality group than those in survivor group (P = 0.004 for genotype, P = 0.010 for allele). Kaplan-Meier survival analysis also showed that patients with the sepsis-associated risk TT genotype at the rs4746720 locus had a lower survival rate than those carrying the TC/CC genotype (log-rank = 7.745, P = 0.005). Another polymorphism rs12778366 was significantly related to 28-day mortality of sepsis, and patients with TT genotype exhibited a greater survival rate than TC/CC genotypes (log-rank = 5.536, P = 0.019). The sepsis-associated risk-T allele of rs4746720 was shown to decrease SIRT1 expression and elevate NF-κB p65 phosphorylation, which was associated with higher expression levels of TNF-α, IL-1β, IL-18 and ICAM-1. Upregulation of SIRT1 led to a notable decrease in LPS-stimulated NF-κB activity and downstream pro-inflammatory cytokine expression in HUVECs.

Conclusions: The current research has yielded significant clinical evidence indicating that the SIRT1 rs4746720 and rs12778366 polymorphisms serve as functional variants with potential utility as prognostic markers for sepsis progression. This may improve the identification of high-risk sepsis patients, thereby facilitating early interventions and optimized treatment strategies.