Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis (original) (raw)
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International …, 2008
Tumour necrosis factor-alpha (TNF α) has been implicated in the pathogenicity of severe sepsis by both genetic association studies and animal models. Conflicting functional data have emerged in relation to genetic variants and TNF α protein production. Therefore, we assessed the functionality of TNF α genetic variants in terms of mRNA production and their potential influence on outcome in the setting of severe sepsis. Sixty-two Irish Caucasian patients presenting with severe sepsis were recruited and TNF α mRNA and protein levels were quantified. Patient DNA was analysed for the presence of common promoter polymorphisms and haplotypes were inferred. An A allele at position-863 was associated with more TNF α mRNA on day 1 compared to C homozygotes (P = 0.037). There was a trend for G homozygotes at position-308 to produce more TNF α mRNA on day 1 than those carrying an A allele (P = 0.059). The presence of an A allele at-863 was associated with greater levels of TNF α mRNA in comparison with patients carrying the A allele at-308 on day 1 (P = 0.02). Patients homozygous for the A allele at position-308 had a higher mortality than those carrying the G allele (P = 0.01). Our data are consistent with recent reports suggesting that a deficient proinflammatory response may be harmful in human sepsis. This deficient inflammatory response may be mediated in part by polymorphisms in the TNF α promoter.
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.
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...
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.
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.
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.
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.
Contribution of genes polymorphism to susceptibility and outcome of sepsis
Egyptian Journal of Medical Human Genetics– Elsevier. 2010;11:97–103.
Sepsis and its sequelae are still a major cause of morbidity and mortality in intensive care units (ICU). The evidence that endogenous mediators actually mediate the individual’s response to infection has led to various approaches to assess the individual’s contribution to the course of the disease. The role of an individual’s genetic background and predisposition for the extent of inflammatory responses is determined by variability of genes encoding endogenous mediators that constitute the pathways of inflammation. Pro- and anti-inflammatory responses contribute to the susceptibility and outcome of patients with systemic inflammation and sepsis. Therefore, all genes encoding proteins involved in the transduction of inflammatory processes are candidate genes to determine the human genetic background that is responsible for interindividual differences in systemic inflammatory responses. Polymorphism of TNA a, TNFB, IL-10, IL-6, IL-1b, IL-1RN, HMGB1, TLR, PAI-1, DEFB1, HSP and MMP-9 has contribution to susceptibility and outcome of sepsis in some research. Examination of the association between genetic polymorphisms and sepsis promises to provide clinicians with new tools to evaluate prognosis, to intervene early and aggressively in treating high risk persons, and to avoid the use of therapies with adverse effects in treating low risk persons. Genomic information may be useful to use to identify groups of patients with a high risk of developing severe sepsis and multiple organ dysfunctions.
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.