Characterization of tumour necrosis factor‐alpha genetic variants and mRNA expression in patients with severe sepsis (original) (raw)
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Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression
BMC Infectious Diseases, 2020
Background The goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-α) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) of TNF-α gene are associated with sepsis in terms of risk, severity and outcome. Methods We performed a prospective study on 163 adult critically ill septic patients (septic shock 65, sepsis 98, further divided in 40 survivors and 123 deceased) and 232 healthy controls. Genotyping of TNF-α SNPs (-308G/A, -238G/A, -376G/A and +489G/A) was performed for all patients and controls and plasma cytokine levels were measured during the first 24 h after sepsis onset. Results TNF-α +489G/A A-allele carriage was associated with significantly lower risk of developing sepsis and sepsis shock (AA+AG vs GG: OR = 0.53; p = 0.004; 95% CI = 0.34–0.82 and OR = 0.39; p = 0.003; 95% CI = 0.21–0.74, respectively) but not with sepsis-related outcomes. There was no significant asso...
Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis
Balkan Medical Journal, 2018
Background: The humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha. Aims: To investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/ del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels. Study Design: Case-control study. Methods: Seventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay. Results: We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05). Conclusion: Our results showed the AA genotype and the A allele of the tumour necrosis factor-alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis.
Tumor Necrosis Factor gene polymorphism results in high TNF level in sepsis and septic shock
Cytokine, 2013
Introduction: Systemic sepsis releases several cytokines among which tumor necrosis factor alfa (TNFa) has emerged as key cytokine causing septic shock. Single Nucleotide Polymorphisms (SNPs) at positions À238, À308, À376 and +489 in the promoter region of TNF gene exhibit differential association to inflammation and increased TNF production in sepsis. Materials and Methods: This research work was carried out in 278 critically ill patients and 115 controls. The patients were divided into four groups: Healthy controls, SIRS, Sepsis and Septic shock. Plasma cytokine level was evaluated by ELISA. Specific sequences of TNF gene (À238, À308, À376, +489) were amplified using polychromase chain reaction (PCR). SNP detected by BamHiI, NcoI, FokI, TaiI restriction enzymes. Results: Mean plasma TNFa level in healthy Control group was 8.37 ± 2.23 pg/ml, in SIRS group, the mean plasma TNFa level was 77.99 ± 5.51 pg/ml, in Sepsis patients 187.1 ± 14.33 pg/ml and in septic shock 202.2 ± 14.85 pg/ml; range 56.17-417.1 pg/ml. SNP was studied among different patient groups, which showed a higher frequency of mutants among sepsis and shock patients as compared to control. Conclusion: Plasma TNF alpha level was significantly high in patients with sepsis and septic shock. SNP of TNF gene showed significant association between polymorphism and development of severe sepsis and septic shock, this would help us in evaluating patients at high risk for septic shock and such patients needed to obtain a rational basis for therapy.
TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study
Genes & Immunity, 2004
Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P ¼ 0.02), sTNFRSF1A (P ¼ 0.005) and sTNFRSF1B (P ¼ 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R ¼ 0.51, Po0.001; sTNFRSF1B R ¼ 0.53, Po0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.
Associations between TNF-α, IL-6 and IL-10 Promoter Polymorphisms and Mortality in Severe Sepsis
Journal of Scientific Research and Reports, 2012
Aims: To determine whether an association exists between TNF-α (rs1800629), IL-6 (rs1800797) and IL-10 (rs180089) promoter polymorphisms and the corresponding systemic cytokine concentrations and outcome in patients suffering from sepsis. Methods: We enrolled 103 consecutive intensive care unit patients with sepsis into a prospective case control study. Blood samples were obtained for extraction of DNA amplifying regions of interest by means of polymerase chain reaction technique (PCR) using specific primers for TNF-α, IL-6 and IL-10. Simultaneously, plasma cytokines and standard laboratory variables were determined during the first 24 h after the diagnosis. Presence of septic shock, sequential organ failure assessment score (SOFA), demographic data and clinical outcome was noticed P < 0.05 was considered as statistically significant. Results: Non-survivors had significantly higher concentrations of TNF-α, IL-6 and IL-10. The carriage of the IL-6-174 and IL-10-1082 polymorphism were associated with a higher risk of mortality in septicemic patients. Presence of the TNF-308 A allele did not influence mortality differently from those lacking this allele. Conclusions: The present study demonstrated an association of the IL-6-174 and the IL-10-1082 polymorphisms with increased mortality in patients suffering from severe sepsis. We found no direct association between the examined polymorphisms and the corresponding cytokine levels.
Journal of Critical Care, 2010
Purpose: The aim of the study was to determine whether distributions of tumor necrosis factor (TNF)α 308 , interleukin (IL)-10 1082 , CD14 159 , and IL-1ra gene intron 2 genotypes in critically ill patients are associated with outcome, underlying cause of sepsis, and type of microorganism. Materials and Methods: Blood samples from 106 critically ill white patients were genotyped by method based on polymerase chain reaction for TNF-α 308 , IL-10 1082 , CD14 159 , and IL-1ra gene intron 2. Results: All patients with TNF-α 308 AA genotype survived; relative risk (RR) of death in patients with AG was 3.250 and with GG, 1.923 (P b .01). In patients with Gram-positive sepsis, IL-10 1082 AA and then AG genotypes were the most frequent ones (odds ratio [OR], 18.67 and 7.20, respectively; P b .01). When comparing IL-10 1082 AA with AG, RR of pancreatitis was 1.80 and OR was 3.40. When AA and GG were compared, RR was 7.33 and OR was 20.00. In patients with GG, RR of peritonitis was 4.07 and OR was 5.88 (P b .01). In patients with Gram-positive sepsis, CD14 159 CT was the most frequent one with OR of 5.25. Distribution of 6 IL-1ra gene intron 2 genotypes showed no significant association. Conclusions: Distribution of TNF-α 308 genotypes is associated with outcome, IL-10 1082 with type of microorganism and underlying cause of sepsis, and CD14 159 with type of microorganism.
Critical Care, 2007
Hydrogen sulfide is produced endogenously by a variety of enzymes involved in cysteine metabolism. Clinical data indicate that endogenous levels of hydrogen sulfide are diminished in various forms of cardiovascular diseases. The aim of the current study was to investigate the effects of hydrogen sulfide supplementation on cardiac function during reperfusion in a clinically relevant experimental model of cardiopulmonary bypass. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or the sodium sulfide infusion (1 mg/kg/hour, n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow, vasodilator responses to acetylcholine and sodiumnitroprusside and pulmonary function were also determined. Administration of sodium sulfide led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 minutes of reperfusion. Coronary blood flow was also significantly higher in the sodium sulfide-treated group (P < 0.05). Sodium sulfide treatment improved coronary blood flow, and preserved the acetylcholine-induced increases in coronary and pulmonary blood (P < 0.05). Myocardial ATP levels were markedly improved in the sulfide-treated group. Thus, supplementation of sulfide improves the recovery of myocardial and endothelial function and energetic status after hypothermic cardiac arrest during cardiopulmonary bypass. These beneficial effects occurred without any detectable adverse hemodynamic or cardiovascular effects of sulfide at the dose used in the current study.
Association of TNF2, a TNF-α Promoter Polymorphism, With Septic Shock Susceptibility and Mortality
JAMA, 1999
EPTIC SHOCK IS THE PRIMARY cause of death in intensive care units (ICUs). With a mortality rate in excess of 50%, it results in more than 100 000 deaths a year in the United States. 1,2 Sepsis-induced organ failure leading to death appears to be due to the activation of a mediator cascade initiated by microbial components. 1,2 Although the pathophysiology of systemic inflammation and organ dysfunction is complex, tumor necrosis factor alpha (TNF-␣) has emerged as a proximal and central cytokine of septic shock. 2,3 Its administration reproduces essentially all the deleterious effects of endotoxin and bacteria, including
TNF -308G > A promoter polymorphism (rs1800629) and outcome from critical illness
Brazilian Journal of Infectious Diseases, 2011
The susceptibility to adverse outcome from critical illness (occurrence of sepsis, septic shock, organ dysfunction/failure, and mortality) varies dramatically due to different degrees of inflammatory response. An over expression of tumor necrosis factor alpha (TNF-α) can lead to the progression of the inflammatory condition.We assessed the relationship of the genotype distribution of -308G >A TNF-α polymorphism with regard to the development of sepsis, septic shock, higher organ dysfunction or mortality in critically ill patients.Observational, hospital- based cohort study of 520 critically ill Caucasian patients from southern Brazil admitted to the general ICU of São Lucas Hospital, Porto Alegre, Brazil. Patients were monitored daily from the ICU admission day to hospital discharge or death, measuring SOFA score, sepsis, and septic shock occurrences. The −308G >A TNF-α SNP effect was analyzed in the entire patient group, in patients with sepsis (349/520), and in those who developed septic shock (248/520).The genotypic and allelic frequencies were −308GG = 0.72; −308GA = 0.27; −308AA = 0.01; −308G = 0.85; −308A = 0.15. No associations were found with sepsis, septic shock, organ dysfunction, and/or mortality rates among the TNF-α genotypes. Our results reveal that the -308G >A TNF-α SNP alone was not predictive of severe outcomes in critically ill patients.The principal novel input of this study was the larger sample size in an investigation with −308G > A TNF-α SNP. The presence of −308A allele is not associated with sepsis, septic shock, higher organ dysfunction or mortality in critically ill patients.
Human Immunology, 2012
Accumulating evidence indicates that genetic background influences the outcome of sepsis, which despite medical advances continues to be a major cause of morbidity and mortality. This study aimed to evaluate the influence of SNPs LTA +252A > G, TNF-863C > A and TNF-308G > A on susceptibility to sepsis, acute respiratory distress syndrome (ARDS), septic shock and sepsis mortality. A prospective casecontrol study was carried out in a Brazilian pediatric intensive care unit and included 490 septic pediatric patients submitted to mechanical ventilation and 610 healthy children. No SNP association was found with respect to sepsis susceptibility. Nevertheless, a haplotype was identified that was protective against sepsis (+252A/À863A/À308G; OR = 0.65; p = 0.03). We further observed protection against ARDS in TNF-308 GA genotype carriers (OR = 0.29; p = 0.0006) and À308A allele carriers (OR = 0.40; p = 0.003). In addition, increased risk for ARDS was detectable with the TNF-863 CA genotype (OR = 1.83; p = 0.01) and the À863A carrier status (OR = 1.82; p = 0.01). After stratification according to age, this outcome remained significantly associated with the À308GA genotype in infants. Finally, protection against sepsis-associated mortality was found for the TNF-308 GA genotype (OR = 0.22; p = 0.04). Overall, our findings document a protective effect of the TNF-308 GA genotype for the ARDS and sepsis mortality outcomes, further providing evidence for an increased risk of ARDS associated with the TNF-863 CA genotype. Trial registration (www.clinicaltrials.gov): NCT00792883.