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"VSports app下载" Clinical significance and prognostic value of SIRT1 genetic variants in sepsis: a multicenter hospital-based case–control study

Clinical Epigenetics volume 17, Article number: 135 (2025) Cite this article

Abstract (V体育官网)

Background

SIRT1 exerts pivotal roles in the pathogenesis of sepsis V体育官网. 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 (V体育官网)

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 VSports手机版. 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 V体育安卓版. This may improve the identification of high-risk sepsis patients, thereby facilitating early interventions and optimized treatment strategies.

Introduction

Sepsis is a severe condition characterized by organ dysfunction caused by an aberrant response to infection, leading to high rates of morbidity and mortality [1]. It is estimated that sepsis contributes to approximately 11 million deaths annually, representing one-fifth of all global mortality [2]. Additionally, sepsis is linked to elevated rates of hospital readmission and places a substantial burden on healthcare systems and society [3, 4]. Research on genetic associations has revealed that variations in inflammation-related genes exert pivotal roles in the pathogenesis of sepsis, highlighting the importance of identifying genetic susceptibility factors in this condition [5,6,7,8,9,10,11] V体育ios版.

Sirtuin 1 (SIRT1), a NAD + -dependent protein deacetylase characterized by a highly conserved amino region, exerts diverse functions primarily through its enzymatic activity in deacetylating histones and non-histones VSports最新版本. Specifically, SIRT1 mediates the removal of acetyl groups from lysine residues on histones and other signaling proteins, leading to chromatin condensation and repression of gene transcription. Additionally, SIRT1 is involved in the deacetylation of transcription factors such as FOXO1, p53 and NF-κB, as well as in the suppression of inflammation-related cytokine secretion (e. g. , IL-6 and TNF-α), oxidative stress and reduction of cellular damage, highlighting its significance as a pivotal factor in the pathophysiology of sepsis [12, 13]. The potential therapeutic approach for managing sepsis involves focusing on SIRT1.

The human Sirt1 gene is situated on the long arm of chromosome 10 (10q21. 3) and is composed of 11 exons V体育平台登录. Recent research has shown that single nucleotide polymorphism (SNP) within SIRT1 can impact cytokine secretion in peripheral blood mononuclear cells (PBMCs) upon exposure to pathogenic microorganisms or lipopolysaccharides [14]. Specifically, a polymorphism at the rs12778366 site (T > C) located in the transcriptional promoter region of the SIRT1 gene has been linked to susceptibility to Parkinson's disease, IL-6-related human mortality and an elevated likelihood of corticosteroid resistance in patients with primary immune thrombocytopenia [15,16,17,18]. Another polymorphism at site rs4746720 (T > C) has been identified as reducing the susceptibility to both coronary artery disease and autoimmune thyroid disease [19, 20]. The potential genetic association between these SIRT1 polymorphisms and sepsis, as well as the mechanisms underlying their impact on sepsis-associated inflammation, remains unexplored.

This multicenter hospital-based case–control study recruited 785 sepsis patients and 776 healthy subjects to evaluate the clinical significance of two SIRT1 genetic SNPs, rs12778366 (T > C) and rs4746720 (T > C), in relation to susceptibility to and progression of sepsis. Subsequent experiments were conducted to analyze the impact of the SIRT1 genetic variants on SIRT1 expression and post-sepsis inflammatory responses. The detailed examination of these sepsis-related functional polymorphisms could potentially leads to novel therapeutic strategies for sepsis VSports注册入口.

"V体育2025版" Methods

Subject enrollment

Sepsis or septic shock was diagnosed in accordance with the definition outlined by the International Conference on Sepsis [21]. Exclusion criteria for the study included patients with sepsis who had underlying hematological diseases, malignancies, chronic illnesses, end-stage conditions, long-term hormone or immunosuppressant use, organ transplant recipients and individuals who expired within 24 h of ICU admission. The healthy control group had no recent acute illnesses, cancer, COPD, diabetes, autoimmune diseases or history of sepsis as indicated in our prior study [5]. Health status was assessed through medical record review and participant or close relative interviews V体育官网入口. A total of 785 sepsis patients and 776 healthy controls from the Han Chinese population, aged over 18 years, were from Jieyang People’s Hospital (Jieyang), Affiliated Hospital of Guangdong Medical University (Zhanjiang), the Fourth Affiliated Hospital of Harbin Medical University (Harbin) and Central Hospital of Wuhan (Wuhan) between May 2017 and November 2023. To control for population stratification, this study enrolled participants based on specific information from their Chinese national resident ID cards, thereby confirming their Han Chinese ethnicity. Interviews were also conducted to rule out the possibility of mixed ethnic backgrounds resulting from intermarriage with non-Chinese populations. Demographic information, infection source, organ dysfunction, blood culture results, sepsis-related organ dysfunction assessment (SOFA) score and acute physiology and chronic health status evaluation (APACHE) II score were documented for each patient, with blood samples obtained within 12 h of sepsis diagnosis. This study was conducted in accordance with the Declaration of Helsinki. Before enrolling, all participants or their guardians gave written consent to participate in the study.

Genotyping of SIRT1 genetic variants

TIANamp DNA extraction kit (Tiangen Biotechnology, China) was used to extract genomic DNA VSports在线直播. Based on the ABI PRISM SNaPshot method, two SIRT1 SNPs were genotyped: rs12778366 and rs4746720. In the PCR amplification of two target fragments (290 and 261, respectively), the following primers were used: 5’-CCACGCAACCAAAGATGGTTTT-3’ (F) and 5’-GCCTGGAGCACAGCGTTTCTATC-3’ (R) for rs12778366; 5’-TTTTCAAAAAGCCATCGGAATGTT-3’ (F) and 5’-AACCGAGTGCTCTCCCCACATA-3’ (R) for rs4746720.

"V体育官网" Mononuclear cell isolation and plasma collection

Density gradient centrifugation with Lymphoprep™ (Axis-Shield PoCAS, Oslo, Norway) was used to isolate peripheral blood mononuclear cells (PBMCs) from 159 randomly selected subjects (86 septic patients and 73 healthy controls) for detection of gene expressions by quantitative real-time PCR (qRT-PCR) V体育2025版. The plasma was also extracted from these blood samples for cytokine measurements by enzyme-linked immunosorbent assay (ELISA).

V体育安卓版 - RNA extraction and qRT-PCR

Total RNA was extracted from PBMCs derived from the randomly selected 86 septic patients and 73 healthy controls using RNAkey™ reagent (Sevenbio, Beijing, China), followed by subsequent reverse transcription and qRT-PCR to detect the expression level of the target genes using SevenFast® Two Step RT&qPCR Kit (Sevenbio, Beijing, China). The primer sequences of SIRT1, TNF-α, IL-27, IL-18, IL-6, IL-1β and β-actin used in this study were presented in Additional file 1. On a 7500 real-time fluorescence quantitative PCR system (Applied Biosystems, Thermo Fisher Scientific, US), 40 cycles of 95°C for 5 s, 58°C for 20 s and 72°C for 33 s were performed. The mRNA expression of each target gene was calculated by the 2−ΔΔCT method and normalized to the expression of β-actin.

Plasmid construction and dual-luciferase reporter gene assay

A 55 bp 3'UTR sequence of SIRT1 gene containing rs4746720 T-to-C mutant was cloned into the pmirGLO luciferase reporter vector (Longqian Biotech, Shanghai, China). The constructed vectors were transfected into 293T cells using lipofectamine 2000 (Invitrogen, USA) according to the manufacturer's instructions. Following a 48-h incubation period, 293T cells were lysed to determine the luciferase activity with the dual-luciferase reporter gene assay kit (Beyotime, Shanghai, China), and measurements were performed using a Synergy H1 full-featured enzyme marker (BioTek, USA).

VSports app下载 - In vitro LPS stimulation experiments on the PBMCs for cytokine measurements

PBMCs derived from another 57 healthy volunteers were cultured in vitro for LPS lipopolysaccharide (LPS) stimulation. Briefly, the cells were seeded in 24-well plates, and cultured in RPMI 1640 medium with fetal bovine serum and antibiotics in a controlled environment. Following an 8-h treatment with 500 ng/mL LPS (L2880; Sigma-Aldrich, USA), the supernatants were isolated for cytokine measurements. Control cells were treated with phosphate-buffered saline (PBS).

SIRT1 overexpression and LPS treatment experiments (V体育ios版)

Human umbilical vein endothelial cells (HUVECs) obtained from the Cell Resource Center, Peking Union Medical College (China), were cultured in endothelial cell medium containing 10% fetal bovine serum (FBS) and 1% penicillin–streptomycin at 37 °C. Overexpression of SIRT1 was achieved using Lentivirus (LV)-SIRT1 (GenePharma, Inc., Shanghai, China) infection in cells, and cells infected with LV-negative control (NC) were set as control. The cells were then stimulated for 6 h with 200 ng/mL LPS.

"V体育ios版" Enzyme-linked immunosorbent assay (ELISA)

The plasma from the 86 cases and 73 controls, as well as the cell supernatants from the in vitro experiment were collected for cytokine measurements including IL-1β, IL-6, IL-18, TNF-α, MCP-1, ICAM-1 and VCAM-1. Each cytokine was analyzed according to the instructions of each specific enzyme-linked immunosorbent assay (ELISA) kit used (ELK Biotechnology, Wuhan, China). Absorbance was measured at 450 nm using a Synergy H1 full-featured enzyme marker (BioTek, USA).

Western blot

The proteins from tissue samples and cells were isolated with RIPA lysate, and the amount of protein in each sample was measured using a BCA protein assay kit from Beyotime Biotechnology in China. Primary antibodies against SIRT1 (1:1000; ab110304, Abcam, UK), p-NF-κB p65 (1:800; sc-136548, Santa Cruz, CA, USA) and β-actin (1:5000; sc-47778, Santa Cruz, CA, USA) were used in this study. The bands were photographed with electrochemiluminescence solution (Biosharp, Beijing, China) and observed using a chemiluminescence imaging system (Tanon 5200 Multi, China). The net density value of each protein band was calculated using ImageJ software (National Institutes of Health, Bethesda, MD).

Immunofluorescence

HUVECs were treated with 4% paraformaldehyde, followed by permeabilization using 0.5% Triton X-100, blocking with 1% BSA and subsequent incubation with NF-κB p65 (1:400; sc-8008, Santa Cruz, CA, USA) primary antibody overnight. Then the samples were incubated with goat anti-mouse secondary antibody (Abbkine Scientific, Wuhan, China). The nuclei were localized and stained by DAPI. The samples were observed under an ECLIPSE Ts2R microscope (Nikon, Japan), and ImageJ software (National Institutes of Health, Bethesda, MD) was used for measurement of NF-κB p65 staining intensities.

Statistical analyses

Statistics analysis was performed using SPSS Statistics 26 software (IBM, NY, USA) and GraphPad Prism 8.0 (GraphPad Software Inc., San Diego, CA, USA). To assess differences in genotype and allele frequencies among groups, the Chi-squared test or Fisher's exact test was used. In the genetic association testing of multiple comparisons, we applied the Benjamini–Hochberg procedure for false discovery rate (FDR) adjustments. This method adjusts p-values to control FDR, helping to identify significant associations while decreasing the risk of type I errors. Kaplan–Meier curves of 28-day ICU survival for sepsis patients were plotted and compared using log-rank tests. All data are presented as mean ± standard deviation (SD). The SIRT1 expression, luciferase activity and cytokine levels were compared between two independent groups using Student's t-test or Mann–Whitney U test. For multigroup comparisons of SIRT1 and cytokine expressions, one-way or two-way ANOVA was employed, followed by Bonferroni post hoc correction to adjust for multiple comparisons. P < 0.05 was considered statistically significant.

"V体育平台登录" Results

Clinical characteristics of the study population

A total of 785 patients diagnosed with sepsis and 776 healthy individuals from four large Chinese general hospitals located in Jieyang, Zhanjiang, Wuhan and Harbin were analyzed in this study. The characteristics of the participants are detailed in Table 1. Among the 785 cases, 53.5% were sepsis subtype and 46.5% were septic shock. The mean age of the healthy controls was 51.05 ± 11.94 years old, and 62.4% were male. The mean age of the patients was 60.70 ± 16.55 years old, and 66.4% were male. Respiratory infections were the most common source of infection (509, 64.8%), followed by abdominal infections (173, 22.0%), blood infections (123, 15.7%) and urinary tract infection (76, 9.7%). With regard to pathogenic bacteria, Acinetobacter baumannii accounted for the majority (25.7%), followed by Pseudomonas aeruginosa (11.7%) and Escherichia coli (11.2%). A 28-day ICU mortality rate of 24.4% was recorded for the septic patients. The average APACHE II and SOFA scores were 25.68 ± 5.80 and 8.44 ± 4.33, respectively.

Table 1 Clinical characteristics of sepsis patients and healthy controls
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Genetic effect of SIRT1 genetic variants on the risk, progression and mortality of sepsis

As shown in Fig. 1A, the human SIRT1 gene is located on chromosome 10q21.3 (67,884,656—67,918,390) and contains 11 exons, with rs12778366 in the promoter region and rs4746720 in the 3'UTR region. The genotypic distribution of the two SNPs in patients and controls conforms to Hardy–Weinberg equilibrium (P > 0.05, Additional file 2). The differences in genotype/allele frequency of SIRT1 genetic variants between the sepsis group and healthy control group were analyzed. The difference in genotype/allele frequency of SIRT1 genetic variants between subgroups of sepsis was also analyzed. As shown in Table 2, patients with septic shock had notably decreased frequencies of rs4746720 TC/CC genotypes and C allele compared to patients with sepsis subtype (P = 0.014 and P = 0.021, respectively). After Benjamini–Hochberg correction, the difference was still statistically significant. With regard to rs12778366, no significant differences in genotypes and allele frequency distributions were observed.

Fig. 1
figure 1

SIRT1 gene expression levels in healthy controls and sepsis patients. A rs12778366 (T > C) and rs4746720 (T > C) are located in the transcriptional promoter region and 3'UTR region of the SIRT1 gene, respectively; B Impact of SIRT1 rs4746720 and rs12778366 on 28-day survival in patients with sepsis by Kaplan–Meier survival analysis; C, D SIRT1 gene expression analysis was performed on sepsis/septic shock related datasets (GSE134347 and GSE131761); E peripheral blood mononuclear cells (PBMCs) from 86 septic patients and 73 healthy controls were extracted for qRT-PCR analysis of SIRT1 expression. SIRT1 gene expression was evaluated between healthy controls and sepsis patients, and AUC of 86 sepsis and 73 healthy samples using ROC analysis for SIRT1 was established in our cohort; F SIRT1 gene expression between sepsis subtype and septic shock groups, AUC of 86 sepsis samples using ROC analysis for SIRT1. Error bar represents standard deviation of the mean (SD)

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Table 2 Genotype and allele frequencies distribution of SIRT1 genetic polymorphisms in the different sepsis status
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We further analyzed the association of SIRT1 gene polymorphisms with 28-day ICU mortality in sepsis patients. In the survivor group, the frequencies of the rs4746720 TC/CC genotype and C allele were notably elevated compared to the mortality group (P = 0.004 for genotype and P = 0.010 for allele; Table 3). After applying the Benjamini–Hochberg correction, these significant differences remained. Interestingly, the frequencies of rs12778366 TC/CC genotype and C allele were significantly lower in survivor group than those in mortality group (P = 0.020 and P = 0.009, respectively), indicating that SIRT1 rs12778366 T > C was also correlated with the prognostic risk of sepsis. Besides, Kaplan–Meier survival analysis showed that patients carrying the 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; Fig. 1B). Patients with the TT genotype at locus rs12778466 exhibited a greater survival rate compared to those with the TC/CC genotypes (log-rank = 5.536, P = 0.019; Fig. 1B).

Table 3 Genotype and allele frequency distribution of SIRT1 gene polymorphisms in sepsis survivor and mortality groups
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However, there were no significant differences between sepsis and control groups (Pgenotype = 0.390 and Pallele = 0.487 for rs12778366, Pgenotype = 0.245 and Pallele = 0.591 for rs4746720; Additional file 3), suggesting that these two genetic variants may not influence the onset of sepsis.

"V体育官网入口" Predictive value of SIRT1 in sepsis patients

In order to elucidate specific alterations in SIRT1 gene expression under septic conditions, differential gene expression analyses were conducted on GSE134347 and GSE131761 datasets related to sepsis and septic shock from the GEO database. The results indicated a significant decrease in SIRT1 gene expression levels in PBMCs from patients with sepsis or septic shock compared to healthy controls or patients with non-septic shock (Fig. 1C, D). In the GSE134347 dataset, SIRT1 had an AUC of 0.784, and in the GSE65682 dataset, it had an AUC of 0.648. Subsequently, a cohort of 86 sepsis patients and 73 healthy individuals were chosen at random for qRT-PCR analysis to investigate the genetic effects of SIRT1 SNPs on SIRT1 expression in sepsis patients and healthy controls. The results in Fig. 1E showed that healthy controls had higher levels of SIRT1 expression compared to patients with sepsis (P < 0.001). The diagnostic model of SIRT1 in our cohort of septic patients and healthy individuals with an AUC of 0.701 further confirmed the previous findings (P < 0.001; Fig. 1E). Further analysis showed that SIRT1 expression in patients with septic shock was significantly lower than those with sepsis subtype (P = 0.004; Fig. 1F). And the diagnostic model of SIRT1 distinguished septic shock from sepsis subtype with an AUC of 0.679 (P = 0.002; Fig. 1F).

V体育平台登录 - Effect of SIRT1 3’UTR polymorphism rs4746720 T > C on SIRT1 expression and downstream NF-κB activity

A further stratified analysis of SIRT1 expression was conducted in 86 sepsis patients and 73 healthy controls based on different SIRT1 genotypes to investigate the association between SIRT1 polymorphisms and SIRT1 expression. Results from qRT-PCR analysis showed that expression level of SIRT1 gene was significantly higher in the rs4746720 TC/CC genotype group than that in the TT genotype group following sepsis (P = 0.022), but no significant difference was observed between different rs4746720 genotypes in healthy controls (Fig. 2A). Regarding rs12778366, no notable differences in SIRT1 expression were detected between different genotypes (Fig. 2B). Considering the significant association of SIRT1 rs4746720 polymorphism with the progression of sepsis as well as SIRT1 expression, we further constructed dual-luciferase vectors containing rs4746720 T-to-C variant to conform the effect of rs4746720 T > C on SIRT1 expression via dual-luciferase reporter gene assay in 293T cells (Fig. 2C, D). As presented in Fig. 2E, cells transfected with pmirGLO-SIRT1-rs4746720-T exhibited significantly lower reporter luciferase activity than cells transfected with pmirGLO-SIRT1-rs4746720-C (P < 0.001). Furthermore, in sepsis patients, PBMCs carrying the rs4746720 TT genotype showed a significant increase in the phosphorylation level of NF-κB p65 compared to those with the CC genotype (P = 0.005) and the combined TC + CC genotypes (P = 0.005) (Fig. 2F, G).

Fig. 2
figure 2

Effect of SIRT1 genetic variants on SIRT1 expression. Peripheral blood mononuclear cells (PBMCs) from 86 septic patients and 73 healthy controls were extracted for qRT-PCR analysis of SIRT1 expression. A Comparison of SIRT1 gene expression between different genotypes of SIRT1 polymorphism of rs12778366 in sepsis patients and healthy controls; B comparison of SIRT1 gene expression between different genotypes of SIRT1 polymorphism of rs4746720 in sepsis patients and healthy controls; C, D SIRT1 3’UTR carrying either the T or C allele of rs4746720 was cloned into the pmirGLO luciferase reporter vectors; E 293T cells were transfected with pmirGLO-rs4746720-T or pmirGLO-rs4746720-C for 48 h and then assayed for luciferase activity using a dual-luciferase reporter assay; F, G the phosphorylation levels of NF-κB p65 in PBMCs from 24 sepsis patients were measured by western blot analysis; each experiment was repeated at least three times independently. Error bar represents standard deviation of the mean (SD)

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Association of SIRT1 genetic variants with pro-inflammatory cytokine expressions in sepsis

We examined the gene expression levels of relevant pro-inflammatory cytokines in PBMCs of 86 selected sepsis patients and 73 healthy controls. Results from qRT-PCR analysis showed that the expression levels of IL-1β (P = 0.010) and TNF-α (P = 0.022), but not IL-6, IL-18 or IL-27, were significantly higher in sepsis patients carrying rs4746720 TT genotype than those with TC/CC genotypes (Fig. 3A-E). No significant differences in expression levels of these inflammatory cytokines were found between different rs12778466 genotypes (All P > 0.05; Fig. 3F-J). We further examined the concentrations of pro-inflammatory cytokines (IL-1β, IL-6, IL-18 and TNF-α) and endothelial injury-associated factors (ICAM-1 and VCAM-1) in the plasma of septic patients by ELISA. As shown in Fig. 4A, septic patients with rs4746720 TC/CC genotypes possessed significantly lower concentrations of IL-1β (P = 0.001), IL-18 (P = 0.046) and TNF-α (P = 0.027) than those carrying TT genotype. However, the concentrations of these pro-inflammatory cytokines in septic patients did not differ significantly between the different genotypes of rs12778366 (Fig. 4B). With regard to endothelial injury-associated factors, the concentration of ICMA-1, but not VCAM-1, was significantly higher in patients with TT genotype than those with TC/CC genotypes (P = 0.017; Fig. 4C). No significant differences in the concentrations of ICAM-1 and VCAM-1 between different genotypes of rs12778366 (Both P > 0.050; Fig. 4D).

Fig. 3
figure 3

Pro-inflammatory cytokine mRNA expression levels in sepsis patients and healthy controls with different SIRT1 polymorphisms. Peripheral blood mononuclear cells (PBMCs) from 159 randomly selected subjects (86 septic patients and 73 healthy controls) were extracted for qRT-PCR analysis. A–E the distribution of IL-1β, IL-6, IL-18, IL-27 and TNF-α expression levels in healthy controls and septic patients with different rs4746720 genotypes; F–J the distribution of IL-1β, IL-6, IL-18, IL-27 and TNF-α expression levels in healthy controls and septic patients with different rs12778366 genotypes. Error bar represents standard deviation of the mean (SD)

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Fig. 4
figure 4

Plasma concentrations of several pro-inflammatory cytokines and endothelial injury-associated factors in septic patients. Plasm from 159 randomly selected subjects (86 septic patients and 73 healthy controls) were extracted for ELISA analysis. A the distribution of IL-1β, IL-6, IL-18, TNF-α, ICAM-1 and VCAM-1 concentrations in septic patients with different rs4746720 genotypes; B the distribution of IL-1β, IL-6, IL-18, TNF-α, ICAM-1 and VCAM-1 concentrations in septic patients with different rs12778366 genotypes. Error bar represents standard deviation of the mean (SD)

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"VSports app下载" Effects of SIRT1 genetic variants on inflammatory cytokine expressions in vitro experiment

We further confirmed the role of SIRT1 genetic variants in inflammatory response in PBMCs from 56 healthy individuals upon in vitro LPS stimulation. Following exposure to 500 ng/mL LPS for 8 h, PBMCs showed a notable increase in production of IL-1β, IL-6 and TNF-α (Fig. 5). When the PBMCs were stratified by different genotypes, the TT genotype of rs4746720 leads to a significant increase in production of IL-1β (P = 0.005), IL-6 (P < 0.001) and TNF-α (P = 0.002) compared with the TC/CC genotypes upon LPS stimulation (Fig. 5A-C). However, no significant differences in the production of these inflammatory cytokines were observed between different genotypes of rs12778366, either with or without LPS stimulation (All P > 0.050; Fig. 5D-F).

Fig. 5
figure 5

Effects of SIRT1 genetic variants on inflammatory cytokine expressions in vitro experiment. PBMCs extracted from 56 randomly selected from the healthy individuals for in vitro LPS stimulation (500 ng/mL, 8 h). A–C The concentrations of IL-1β, IL-6 and TNF-α upon LPS stimulation in cultural supernatant of PBMCs with different rs4746720 genotypes were measured by using ELISA; D–F the concentrations of IL-1β, IL-6 and TNF-α upon LPS stimulation in cultural supernatant of PBMCs with different rs4746720 genotypes were measured by using ELISA. Error bar represents standard deviation of the mean (SD)

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Effects of SIRT1 on NF-κB activity and the downstream inflammatory response

We further confirmed the role of SIRT1 in LPS-induced NF-κB activity and inflammatory response. Following exposure to 200 ng/mL of LPS for 6 h, cells showed a notable reduction in SIRT1 expression, while demonstrating a marked rise in the NF-κB activity and expression levels of pro-inflammatory cytokines (Fig. 6). When SIRT1 was overexpressed via transfection of LV-SIRT1, the expression levels of IL-1β (P < 0.001), IL-6 (P = 0.022), TNF-α (P = 0.009) and ICAM-1 (P < 0.001) were significantly decreased upon LPS stimulation (Fig. 6A-C). SIRT1 overexpression resulted in a significant decrease in phosphorylation and nuclear translocation of NF-κB p65 in HUVECs following LPS stimulation (Fig. 6D, E).

Fig. 6
figure 6

Effects of SIRT1 overexpression on NF-κB activity and downstream inflammatory response in HUVECs. Expression of SIRT1 and pro-inflammatory cytokines as well as vascular injury factor and NF-κB activity in SIRT1 overexpressing HUVECs were determined after 6 h of LPS stimulation (200 ng/mL). A Expression of SIRT1, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, MCP-1) and vascular injury factors (ICAM-1, VCAM-1) in HUVECs with qRT-PCR analysis; B, C protein production of SIRT1 and p-NF-κB p65 in HUVECs with western blot analysis; D, E immunofluorescence assay showed the effect of SIRT1 overexpression on NF-κB nuclear translocation in HUVECs. Each experiment was repeated at least three times independently. Error bar represents standard deviation of the mean (SD)

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V体育官网入口 - Discussion

This study examined the clinical relationship between sepsis and two genetic variants (rs12778366 and rs4746720) in the SIRT1 gene for the first time. The findings revealed a significant association between the rs4746720 T > C polymorphism in the SIRT1 3’UTR region and sepsis-related inflammatory responses, progression of sepsis and unfavorable outcomes. The presence of the risk-T allele of rs4746720 was shown to downregulate SIRT1 expression, leading to the enhanced inflammatory responses. This genetic detrimental effect ultimately increased the risk of sepsis progression and mortality.

SIRT1, a member of the Sirtuin family, plays a crucial role in regulating gene expression through the deacetylation of histone and non-histone lysine residues. Its substrates, including molecules such as FOXO1, NF-κB and p53, have been shown to be involved in various cellular processes [12, 13]. During sepsis, SIRT1 inhibits inflammatory cytokine expression in immune cells, leading to the suppression of inflammation and oxidative stress, modulation of metabolism and reduction of sepsis-induced organ damage [22, 23]. These effects are mediated through the regulation of signaling pathways such as NF-κB and PI3K/Akt, highlighting the importance of SIRT1 as a key regulator in the pathogenesis of sepsis [24, 25]. SIRT1 levels have been found to be reduced in patients with sepsis and in models of sepsis, and correlate with disease progression [26,27,28,29,30]. SIRT1 deficiency increases systemic inflammatory responses, organ damage and mortality in septic mice [31, 32]. The findings of this study indicate a notable decrease in SIRT1 expression in sepsis patients, consistent with previous research by Lin X et al. [26]. Additionally, gene expression analysis conducted by Sun M et al. highlights the importance of SIRT1 as a key gene in sepsis-induced ARDS [33]. This study suggests that SIRT1 plays a crucial role in the progression of sepsis, with its levels decreasing as the disease advances. Furthermore, the ability of SIRT1 to differentiate sepsis from normal samples with an AUC of 0.701 suggests its potential as a marker for assessing sepsis severity.

A recent genetic association study has indicated that the rs4746720 single nucleotide polymorphism (SNP) located in the SIRT1 3'-UTR region may impact mRNA expression through its interaction with miR-599, potentially increasing the risk of acute kidney injury in individuals with liver cirrhosis [34]. Sarumaru M et al. also observed that individuals carrying the T allele at the SIRT1 rs4746720 locus exhibited higher levels of thyroid autoantibodies in patients with Graves' disease compared to those with the CC genotype [20]. Additionally, the SIRT1 rs12778366 polymorphism has been found to have a negative association with the development of diabetic foot [35]. However, the role of SIRT1 SNPs in the pathogenesis of sepsis has not been determined to date. Patients with septic shock showed lower rs4746720 TC/CC genotype and C allele frequencies than those with sepsis subtype. After Benjamini–Hochberg correction, this difference held statistical significance.

Furthermore, the observation of a higher frequencies of rs4746720 TC/CC genotype carriers compared to TT genotype carriers in the survivor group supports the hypothesis that rs4746720 T > C might be a potential protective factor for clinical prognosis in sepsis patients. With regard to rs12778366, no significant difference in genotype/allele frequencies between sepsis subtype and septic shock was found. Furthermore, patients carrying TC/CC genotypes of rs12778366 exhibited a worse clinical prognosis than those with TT genotype, indicating a risk role of rs12778366 T > C in prognosis of sepsis. However, there were no statistically significant differences in genotype/allele frequencies of rs12778366 T > C and rs4746720 T > C polymorphisms between sepsis patients and healthy controls, suggesting that these genetic variations might not play a significant role as risk factors for the onset of sepsis. We further detected the expression of SIRT1 in PBMCs derived from the sepsis patients and healthy controls by qRT-PCR to evaluate the association of these SNPs with SIRT1 expression. In sepsis patients, individuals with the rs4746720 TC/CC genotype exhibited a notable increase in SIRT1 expression compared to those with the TT genotype, indicating a potentially protective role of rs4746720 T > C in the pathogenesis of sepsis through its impact on SIRT1 expression. However, no significant difference in SIRT1 expression was observed between rs4746720 genotypes in healthy controls, likely due to the low baseline expression in the absence of disease, which further supports that rs4746720 T > C may primarily affect sepsis progression rather than its onset. With regard to rs12778366, no significant disparity in SIRT1 expression was observed among patients with different genotypes.

To ascertain whether the association between rs4746720 T > C and SIRT1 expression represented a direct regulatory effect, we conducted an in vitro dual-luciferase assay to evaluate the functional impact of the rs4746720 T-to-C variant on SIRT1 expression. Our results demonstrated that the luciferase vector containing the sepsis-associated protective C allele exhibited significantly higher luciferase activity compared to the T allele, thereby supporting the regulatory effect of rs4746720 T-to-C variant on SIRT1 expression. Recent research has demonstrated that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) can modulate the expression of SIRT1 messenger RNAs (mRNAs) and proteins by interacting with the 3’UTR of SIRT1 [34, 36, 37]. Since rs4746720 is located in the 3’UTR of SIRT1, alterations in miRNA binding to this specific region due to T-to-C variant may contribute to the regulation of SIRT1 expression. Further research is needed to clarify the molecular mechanisms underlying the influence of rs4746720 T-to-C variant on SIRT1 expression and its role in sepsis pathogenesis.

Multiple studies have implicated SIRT1 in inflammation development and progression [38,39,40]. Shen et al. conducted a study on the impact of lipopolysaccharides (LPS) on the release of TNF-α by macrophages, revealing that SIRT1 plays a significant role in inhibiting TNF-α expression in the presence of agonists [41]. Suppression of SIRT1 expression or utilization of SIRT1-siRNA to silence the SIRT1 gene in cells can lead to an increase in TNF-α expression. SIRT1 activator also inhibited the overexpression of pro-inflammatory factors MMP-9, IL-1β, IL-6 and iNOS in TNF-α-induced cell damage [42]. Furthermore, SIRT1 can suppress NF-κB signaling via inhibition of NF-κB-p65 acetylation and phosphorylation to inhibit the inflammatory responses [24, 43]. To ascertain the impact of functional SIRT1 genetic variants on the NF-κB activity and downstream inflammatory responses, the NF-κB p65 phosphorylation, and IL-1β, IL-6, IL-18, IL-27 and TNF-α expression levels were examined. In sepsis patients, PBMCs with the rs4746720 TT genotype exhibited significantly higher phosphorylation of NF-κB p65 compared to those with TC + CC genotypes. The results of ELISA analysis showed that sepsis patients who possessed the rs4746720 T allele exhibited significantly higher plasma levels of pro-inflammatory cytokines (IL-1β, IL-18 and TNF-α) and vascular injury-associated factor (ICAM-1) compared to those with the T allele. However, rs12778366 T > C did not produce significant differences in pro-inflammatory and endothelial injury-associated factors. We further confirmed the effect of SIRT1 genetic variants on inflammatory response in PBMCs upon in vitro LPS stimulation by ELISA analysis. Consistently, the TT genotype of rs4746720 leads to a significant increase in production of IL-1β, IL-6 and TNF-α compared with the TC/CC genotypes upon LPS stimulation. These findings indicated that the sepsis-associated risk rs4746720 T allele might enhance NF-κB activity and downstream inflammatory responses through its inhibitory effect on SIRT1 expression, ultimately conferring susceptibility to the progression and poor prognosis of sepsis. To corroborate this observation, we conducted cell experiments to assess the impact of SIRT1 expression on LPS-induced NF-κB activity and downstream inflammatory responses. Our findings indicated that SIRT1 overexpression led to a significant reduction in the phosphorylation and nuclear translocation of NF-κB p65, as well as a decrease in pro-inflammatory cytokine expression in LPS-stimulated HUVECs. These results provide compelling evidence for the therapeutic potential of SIRT1 in sepsis treatment. Specifically, personalized SIRT1-activated therapy may represent a viable strategy for sepsis patients with the high-risk TT genotype of SIRT1 rs4746720, which is characterized by diminished SIRT1 expression levels, thus presenting a promising opportunity for precision medicine in sepsis management.

Several limitations should be acknowledged in this study. Firstly, it is important to note that the current case–control study design with cross-sectional in nature, while valuable for identifying associations, limits the ability to infer causality. It may also be prone to confounding biases, with unmeasured variables potentially influencing the potential causal role of SIRT1 SNPs in the pathophysiology of sepsis. Secondly, even though we strictly enrolled subjects following inclusion and exclusion criteria to increase sample homogeneity, the preexisting complications in septic patients may have contributed to different SNP-associated observations. Thirdly, we cannot rule out the possibility that other nearby functional SNPs, in linkage disequilibrium with the SIRT1 SNPs, may contribute to the observed association with sepsis. Fourthly, a notable strength and limitation of our study is that all samples were derived from the Han Chinese population. Although the homogeneous Han Chinese population enhances the power and validity of our analyses within this group, the lack of replication in an independent dataset limits the generalizability to other ethnicities. Thus, further validation in independent, larger populations and across different ethnic backgrounds is required before defining and generalizing the conclusions. Finally, only two SIRT1 genetic variants were analyzed for their impact on sepsis. It is conceivable that additional functional polymorphisms may also influence SIRT1 expression, thus warranting further investigation into their collective effects to enhance the accuracy of assessing individual susceptibility to sepsis onset or progression.

Conclusions

This study demonstrated a notable correlation between rs4746720 T > C polymorphism in the SIRT1 3’UTR region and sepsis progression as well as clinical outcomes. Another polymorphism of rs12778366 T > C in the SIRT1 promoter is linked to poor sepsis prognosis. The sepsis-associated risk rs4746720 T allele might enhance inflammatory responses via its inhibitory effect on SIRT1 expression, ultimately conferring susceptibility to the progression and poor prognosis of sepsis. Integrating this genetic marker into risk stratification models might enhance the identification of high-risk sepsis patients, thereby facilitating early intervention and optimized treatment strategies. Specifically, identifying sepsis patients carrying the risk rs4746720 T allele, which is associated with lower SIRT1 expression, may benefit from implementation of individualized precision therapies, such as SIRT1-specific agonists or supplementation.

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All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

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Funding

This research was funded by Guangdong Basic and Applied Basic Research Foundation (2024A1515012890, 2023A1515012477, 2025A1515010689), China Health Promotion Foundation, Medical Scientific Research Foundation of Guangdong Province (A2023230, A2023272), National Natural Science Foundation of China (82302446, 82470811) and Affiliated Hospital of Guangdong Medical University Clinical Research Program (LCYJ2019A002).

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  1. Junbing He, Meiting Yang, Yao Lin have contributed equally to this work.

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  1. Jieyang Medical Research Center, Jieyang People’s Hospital, Jieyang, Guangdong, China

    Junbing He, Yao Lin, Wanbing Qin, Ruoxuan Yang, Mingwei Xu & Qinghua Liu

  2. The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China

    Meiting Yang, Yuting Qin & Yiming Shao

  3. The Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang,, Guangdong, People’s Republic of China

    Meiting Yang, Yuting Qin, Lizhen Liu & Yiming Shao

  4. Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Qinghua Liu

  5. NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China

    Qinghua Liu

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"V体育官网" Contributions

JH, QL and YS contributed to the study conception and design. Material preparation, data collection and analysis were performed by JH, MY, YL, WQ, RY, YQ, LL and MX. The first draft of the manuscript was written by JHe, MY, YL, WQ, RY, YQ and LL. The manuscript was reviewed and revised by JH, QL, YS and MX, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junbing He, Yiming Shao or Qinghua Liu.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Jieyang People’s Hospital, Affiliated Hospital of Guangdong Medical University, the Fourth Affiliated Hospital of Harbin Medical University (Harbin) and Central Hospital of Wuhan. Informed consent was obtained from all individual participants included in the study.

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He, J., Yang, M., Lin, Y. et al. Clinical significance and prognostic value of SIRT1 genetic variants in sepsis: a multicenter hospital-based case–control study. Clin Epigenet 17, 135 (2025). https://doi.org/10.1186/s13148-025-01944-7

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