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Evaluation of TNF-? genetic polymorphisms as predictors for sepsis susceptibility and progression.

ABSTRACT: BACKGROUND:The goal of the study was to evaluate a potential role for tumor necrosis factor alpha (TNF-?) genetic variability as biomarker in sepsis. In particular, we aimed to determine if single nucleotide polymorphisms (SNPs) of TNF-? 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-? 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-??+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 association between any of the other TNF-? promoter SNPs, or their haplotype frequencies and sepsis or septic shock risk. Circulating TNF-? levels were higher in septic shock; they were not correlated with SNP genotype distribution; GG homozygosity for each polymorphism was correlated with higher TNF-? levels in septic shock. CONCLUSIONS:TNF-??+489G/A SNP A-allele carriage may confer protection against sepsis and septic shock development but apparently does not influence sepsis-related mortality. Promoter TNF-? SNPs did not affect transcription and were not associated with distinct sepsis, septic shock risk or outcomes.

SUBMITTER: Georgescu AM

PROVIDER: S-EPMC7071754 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression.

Georgescu Anca Meda AM Banescu Claudia C Azamfirei Razvan R Hutanu Adina A Moldovan Valeriu V Badea Iudita I Voidazan Septimiu S Dobreanu Minodora M Chirtes Ioana Raluca IR Azamfirei Leonard L

BMC infectious diseases 20200314 1

<h4>Background</h4>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.<h4>Methods</h4>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 hea ...[more]

PMID: 32171247

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Project description:BackgroundTumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-? (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population.Methodology/principal findingsTen SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P(adj) = 0.00046, odds ratio (OR)(adj) = 1.92) and sepsis patients (P(adj) = 0.002, OR(adj) = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-? concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-? serum levels in severe sepsis patients. After exposure to LPS, the TNF-? concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-? serum concentrations than those with GG genotype (P(adj) = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.Conclusions/significanceOur findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.

Project description:Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates the crucial role of TNF-α in autoimmune pathogenesis of vitiligo.

Project description:ObjectiveTo investigate the relationship between polymorphism of TNFRSF11 gene rs9533156 and rs2277438 and susceptibility to gastric cancer.MethodsA case-control study was conducted to select 577 cases of primary gastric cancer and 678 cases of normal control. We extracted whole blood genomic DNA and amplified the target gene fragment by PCR. The genotyping and allele were tested through the snapshot method.ResultsIn this case-control study, we observed that there was a difference in the genotype distribution of TNFRSF11 gene rs9533156 between the case group and the control group. The frequency distribution of TC heterozygous mutation in the case group was higher than that in the control group. The smoking rate in the case group (34.49%) was higher than that in the control group (27.29%), and the difference in frequency distribution between the two groups was statistically significant (P=0.006). Our findings suggest that TNFRSF11 rs9533156 is associated with susceptibility to GC, which is more evident among elderly patients (>62 years), nonsmokers, and patients who do not consume alcohol. The analysis of the relationship between the TNFSF11 gene rs9533156 site variant and clinical factors of gastric cancer showed that, compared with the tumor size <2 cm group, patients with tumor size ≥2 cm and whom carrying rs9533156 site mutations had a higher frequency distribution, and the difference was statistically significant (P=0.022). Compared with the nonhyperglycemic group, the frequency distribution of patients with rs9533156 site mutations in the diabetes group was higher, and the difference was statistically significant (P < 0.001).ConclusionThis study shows that there is a correlation between smoking and the occurrence of gastric cancer. Based on our research, the functional SNP TNFRSF11 TC genotype may be an indicator of individual susceptibility to GC. The mutation at rs9533156 may be related to the size of gastric cancer. The mutation rate of rs9533156 of TNFSF11 gene is higher in diabetic gastric cancer patients.

Project description:BackgroundRecent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population.MethodsFourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA).ResultsThe association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P = 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37-0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P = 0.012 and P = 0.003, respectively) as well as after LPS stimulation (P = 0.009 and P = 0.005). Moreover, the concentrations of TNF-α and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases.ConclusionsOur findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI.

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Evaluation of TNF-? genetic polymorphisms as predictors for sepsis susceptibility and progression.

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Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression.

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