Polymorphism in the tumor necrosis factor-α gene promoter is associated with severity of rheumatoid arthritis in the Czech population

Rheumatoid arthritis (RA) is a model of multigenic inflammatory disorder in which tumor necrosis factor-α (TNF-α) plays an important role. Genetic factors may be implicated in the susceptibility to disease initiation as well as in severity of disease course. Elevated levels of TNF-α in the plasma and synovial fluid from RA patients may be associated with polymorphisms in the promoter region of the TNF-α gene. The aim of this study was to elucidate putative association between the −308 G/A polymorphism in the promoter region of the TNF-α gene and susceptibility to onset and severity of RA. A total of 130 RA patients and a control group of 150 healthy subjects with similar age and sex distribution were available for the study. All patients fulfilled the American College of Rheumatology revised criteria for RA. RA patients had a disease duration of at least 2 years. Radiographs of both hands of all RA patients were scored with the Steinbrocker method. There were 15 patients of stage I (nonerosive form) of RA and 114 patients of stages II–IV (erosive form). To assess the RA patient’s functional ability, the Health Assessment Questionnaire (HAQ) was used. The −308 G/A promoter polymorphism of the TNF-α gene was detected by polymerase chain reaction and restriction fragment length polymorphism analysis. No differences in genotype distribution and allelic frequences of −308 G/A TNF-α promoter polymorphism have been found between RA patients and the control group. Significant differences have been observed within the RA group divided according to the radiographic progression of disease based on the Steinbrocker radiographic score and functional ability (HAQ). These results suggest an association of the −308 G/A polymorphism of the TNF-α gene with the severity of RA.     

Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: a meta-analysis

Background and Aim: Environmental and genetic factors play a role in the pathogenesis and natural history of non‐alcoholic fatty liver disease (NAFLD). The objective of this study was to quantitatively evaluate the association between tumor necrosis factor (TNF)‐α gene promoter polymorphism at sites ‐308 and ‐238 and NAFLD susceptibility. Methods: We performed an extensive search of relevant studies and made a meta‐analysis, including eight studies with 837 NAFLD cases and 990 controls in the association between TNF‐α ‐308 polymorphism and NAFLD; and seven studies with 771 cases and 787 controls in TNF‐α ‐238 polymorphism. Results: The combined results showed that there was a significant difference in TNF‐α‐238 genotype distribution between NAFLD and control based on all studies (GA/AA vs GG [odds ratio = 2.06, 95% confidence interval = 1.58–2.69, P < 0.000 01]). However, the combined results based on all studies showed there was no evidence of association of TNF‐α‐308 genotype distribution between NAFLD cases and controls (GA/AA vs GG [odds ratio = 1.08, 95% confidence interval = 0.82–1.42, P = 0.60]). When stratifying for race, the significant results did not change materially compared with whole populations. Conclusion: This meta‐analysis suggested that TNF‐α gene promoter polymorphism at position ‐238 but not ‐308 might be a risk factor for NAFLD.     

The relationship between tumor necrosis factor-α gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome

Objective To investigate the relationship between tumor necrosis factor-α(TNF-α) gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods The plasma TNF-αlevel of OSAHS group and non-OSAHS group was detected by enzyme-linked immunosorbent assay (ELISA). Eighteen patients with severe OSAHS were treated with continuous     

Association of G-308A TNF-α Polymorphism with Bronchial Asthma in a North Indian Population

Bronchial asthma is an inflammatory disorder in which genetic and environmental factors play an important role. Several susceptible genes have been identified using whole genome scan and candidate gene approaches. Tumor necrosis factor alpha, a pro-inflammatory cytokine, is one such gene that figures prominently in such investigations. The secreted levels of this cytokine are under genetic control and attributed to the presence of single nucleotide polymorphism G-308 A in the promoter region of its gene. However, the association of this polymorphism varies from population to population. As there are no data available on North Indians, the present study aims to fill this void. For this, 366 subjects (155 asthmatic and 211 normal control subject) were genotyped using Amplification Refractory Mutation System Analysis (ARMS–PCR) and agarose gel electrophoresis. The distribution of G/A alleles between the two groups revealed statistically significant differences (p = 0.016). Furthermore, the asthma patients categorized on the basis of pattern (Seasonal versus Perennial) and age of onset of disease (Childhood versus Late Onset) revealed significant association with only seasonal (p = 0.021) and late onset asthmatic groups (p = 0.039). The data from the present study strongly suggest an association between TNF-α and asthma in the North Indian population.     

Correlation between the concentrations of tumor necrosis factor-α and the severity of disease in patients infected with Orientia tsutsugamushi

BackgroundPatients with tsutsugamushi disease sometimes die if they do not receive appropriate chemotherapy. This study measured the concentration of several cytokines both before and after the administration of tetracyclines, and evaluated the changes in cytokine levels in patient serum to investigate the relationship between serum levels of cytokines and disease severity.MethodsA total of nine patients were infected with Orientia tsutsugamushi. The diagnosis of tsutsugamushi disease was made using an indirect immunoperoxidase antibody test. The serum concentrations of cytokines were measured using enzyme-linked immunosorbent assays.ResultsThe levels of interleukin (IL)-10 (mean 71.7 pg/ml) and IL-12p40 (mean 588 pg/ml) were elevated in all patients in the acute phase, above the normal upper limits. Tumor necrosis factor-α (TNF-α) levels (mean 9.20 pg/ml) were elevated in 89% and interferon-γ (IFN-γ) levels (mean 41.0 pg/ml) in 44% of patients. The down-regulation of these overproduced cytokines was observed after chemotherapy. There was a significant correlation between the concentrations of TNF-α in the acute phase and the severity of disease (r = 0.918).ConclusionThe concentration of TNF-α may predict the severity of tsutsugamushi disease in the acute infectious phase.     

Tumor necrosis factor-α and tumor necrosis factor receptors in human heart failure

The basic mechanisms that are responsible for the development and progression of congestive heart failure are not known. Although clinicians have traditionally viewed heart failure as a hemodynamic disorder related to left ventricular pump dysfunction, one of the more recent concepts that has emerged is that the development and progression of heart failure is attributable, at least in part, to the overexpression of biologically active molecules that can contribute both to patient symptomatology as well as to disease progression. In this regard, one of the more recent interesting and intriguing observations in clinical heart failure research is the finding that a proinflammatory cytokine, termed tumor necrosis factor- (TNF-), is expressed in patients with heart failure. Accordingly, the focus of the present brief review is to summarize recent clinical and experimental observations that implicate the elaboration of TNF- and TNF receptors in the progression of human heart failure.     

Risk of hepatitis B reactivation in patients treated with tumor necrosis factor-α inhibitors

The use of tumor necrosis factor-α (TNF-α) inhibitors has been increasing especially in patients with rheumatoid arthritis (RA). As TNF-α inhibitors are strongly immunosuppressive, the occurrence of hepatitis B virus (HBV) reactivation has recently been observed. Reports suggest a higher risk of complicating HBV reactivation in carriers who are treated with TNF-α inhibitors. Therefore, HBV carriers are recommended to undergo prophylactic administration of nucleos(t)ide analogs (NAs). Our literary analysis uncovered several characteristics of de novo hepatitis B due to TNF-α inhibitors. First, the time between the start of TNF-α inhibitors and the occurrence of de novo hepatitis was longer than one year. Second, patients were usually treated with additional non-biologic agents, which also had immunosuppressive effects. Third, the disease could be fatal. Fourth, several types of TNF-α inhibitors exhibited a risk of developing de novo hepatitis. Although the incidence of de novo hepatitis B varied among reports (0-5%/year), it is suggested that patients with prior HBV infection are at risk of developing de novo hepatitis due to TNF-α inhibitors. Many reports maintain that regular measurement of HBV DNA is effective in preventing de novo hepatitis. Prophylactic administration of NAs is also considered useful to avoid de novo hepatitis, although the issue of cost-effectiveness needs to be addressed. Lastly, whereas maintenance of circulating anti-HBs titer using HB vaccines may be effective in responders to prevent de novo hepatitis, further studies are required to clarify the utility of HB vaccination.     

Plasma levels of tumor necrosis factor-α and its receptors in patients with mitral stenosis and sinus rhythm undergoing percutaneous balloon valvuloplasty

This study aimed to determine whether plasma levels of tumor necrosis factor-α (TNF-α) and soluble TNF receptor (sTNF-R) increases in rheumatic mitral stenosis (MS) patients with sinus rhythm and to examine the effect of percutaneous mitral balloon valvuloplasty (PMBV) on these parameters. Twenty-six patients with MS and sinus rhythm (study group, 20 female, mean age 33 ± 8 years), who were scheduled for PMBV, and a well-matched control group consisting of 21 healthy volunteers (15 female, mean age 35 ± 6 years) were enrolled in the study. Tumor necrosis factor-α and sTNF-R levels were compared between study patients and controls, and between peripheral and left atrium (LA) blood. Changes in TNF α and sTNF-R levels 24 h and 4 weeks after PMBV were analyzed. Significantly higher baseline TNF-α and sTNF-R levels were noted in the study group. In the study group, TNF-α and its receptors were also found to be higher in LA blood than in baseline peripheral blood. After PMBV, mitral valve area (MVA) increased and transmitral pressure gradient decreased significantly. At the 24th hour after PMBV, the TNF-α level decreased from 29.61 ± 12.22 pg/ml to 22.42 ± 8.81 pg/ml (P < 0.0001) and at the 4th week, from 22.42 ± 8.81 pg/ml to 18.92 ± 7.37 pg/ml (P < 0.0001). Similar reductions were observed in the sTNF-R level. Regression analysis between the difference in sTNF-R level measured 24 h after and before PMBV and the difference in MVA measured 24 h after and before PMBV showed a significant direct relationship between these variables. This study suggests that isolated rheumatic MS without atrial fibrillation is accompanied by increased TNF-α and sTNF-R level. The successful PMBV establishes a significant reduction in TNF-α and its receptors, probably due to improved postprocedural hemodynamic parameters.     

Systematic review and meta-analysis on the association of tuberculosis in Crohn's disease patients treated with tumor necrosis factor-α inhibitors(Anti-TNFα)

AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis(TB) infection in Crohn's disease(CD) patients treated with tumor necrosis factoralpha(TNFα) inhibitors.METHODS A meta-analysis of randomized, double-blind, placebocontrolled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction(EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028(95%CI: 0.0011-0.055). The odds ratio was 4.85(95%CI: 1.02-22.99) with EBC and 5.85(95%CI: 1.13-30.38) without EBC.CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.     

Tumor necrosis factor-α -308 polymorphism in North Indian rheumatoid arthritis patients and association with mRNA and serum TNF-α

Rheumatoid arthritis (RA) is a severely disabling chronic autoimmune disorder that leads to progressive inflammation of the joints and surrounding tissues. TNF-α, a potent proinflammatory cytokine, plays a pivotal role in the pathogenesis of RA. The endogenous formation of TNF-α may be influenced by TNF-α promoter polymorphisms. Hence, the present study was designed to explore any possible association between genetic polymorphism of TNF-α -308 G/A, messenger RNA (mRNA) expression, serum levels of TNF-α, and inflammatory markers in North Indian RA patients. A total of 214 controls and 187 RA patients were recruited according to the revised American College of Rheumatology 2010 criteria. TNF-α -308 G/A genetic polymorphism within promoter region was analyzed by using PCR-RFLP. Levels of inflammatory markers and serum TNF-α were estimated by ELISA. The mRNA expression of TNF-α gene was measured by quantitative real-time PCR. Higher levels of autoantibodies (RF and anti-CCP) were present in RA patients as compared to controls. We found a positive and significant correlation of circulating TNF-α levels with RF (r = 0.18), anti-CCP (r = 0.16), and mRNA expression of TNF-α gene (r = 0.57) in RA patients. The mRNA expression levels of TNF-α was 4.5-fold higher in patients with RA as compared to controls. The heterozygous mutant variants (G/A) and homozygous mutant variants (A/A) were found to be significantly associated with RA as compared to control (OR = 1.52 and 3.02, respectively). Our observations illustrated a significant association of allele -308 A TNF-α with progression of RA. Significant and positive correlation of TNF-α levels with mRNA expression and inflammatory marker levels suggests that serum TNF-α may be a susceptibility marker for RA.     

Association between tumor necrosis factor-α (TNF-α) promoter −308 G/A and response to TNF-α blockers in rheumatoid arthritis: a meta-analysis

Abstract

Objectives Tumor necrosis factor (TNF)-α promoter ?308G/A polymorphism has been shown to be associated with high TNF-α production and poor response to anti-TNF-α treatment. However, not all patients show a good response to TNF-α antagonists, so this association remains controversial. This study was designed to investigate whether TNF-α promoter ?308 G/A polymorphism is associated with responsiveness to anti-TNF therapy in rheumatoid arthritis (RA) patients. The 28-joint count Disease Activity Score (DAS) 28 or the American College of Rheumatology (ACR) improvement criteria 20 were used to measure patient response.

Methods A meta-analysis was performed. Pooled ORs and 95 % CIs were calculated by both dominant and recessive genetic models.

Results Fifteen studies with a total of 2127 patients were included in this meta-analysis. The results showed that patients with the G allele responded better to the treatment (OR = 1.87, 95 % CI 1.26–2.79). A subanalysis showed similar results.

Conclusions Based on the results of this meta-analysis, RA patients with the TNF-α promoter ?308 G allele respond better to TNF-α antagonist treatment, suggesting that this allele plays a major role in anti-TNF-alpha treatment response.     

Expression of the tumor necrosis factorα gene and early response genes by nodularin, a liver tumor promoter, in primary cultured rat hepatocytes

Nodularin is a new liver carcinogen possessing a potent tumor-promoting activity in rat liver, mediated through inhibition of protein phosphatases 1 and 2A, and a weak initiating activity. Since we previously reported evidence that nodularin up-regulated expression of the tumor necrosis factor gene (TNF) and early-response genes in rat liver after its i.p. administration, and since TNF had tumor-promoting activity in vitro, it is possible that TNF itself is involved in liver tumor promotion. We investigated whether hepatocytes themselves induce expression of theTNF gene and early-response genes in primary cultured rat hepatocytes treated with nodularin. Like nodularin, microcystin-LR, which is another liver tumor promoter belonging to the okadaic acid class, strongly inducedTNF gene expression in rat hepatocytes, as well as TNF release from those cells into the medium. On the other hand, 12-O-tetradecanoylphorbol-13-acetate, which has been reported to induce no tumor promotion in rat liver, induced no apparent expression of theTNF gene in primary cultured rat hepatocytes. As for the expression of early-response genes, 1 M nodularin or microcystin-LR induced expression of the c-jun, jun B,jun D, c-fos, fos B andfra-1 genes in the hepatocytes, and the expression of these genes was prolonged up to 24 h, suggesting mRNA stabilization induced by inhibition of protein phosphatases 1 and 2A. This paper presents new evidence that theTNF gene and early-response genes were expressed in hepatocytes treated with a liver tumor promoter.Abbreviations GST-P glutathioneS-transferase placental form - TNF tumor necrosis factor - GAPDH glyceraldehyde-3-phosphate dehydrogenase - SSC standard saline citrate - SDS sodium dodecyl sulfate - TPA 12-O-tetradecanoylphorbol-13-acetate     

Effect of tumor necrosis factor-α antagonists on oxidative stress in patients with Crohn's disease

AIM: To investigate changes in oxidative stress in Crohn's disease(CD) before and after anti-tumor necrosis factor(TNF)-α treatment.METHODS: A total of 42 patients with active CD, who were scheduled to be treated by anti-TNF-α antibodies, were enrolled. Serum levels of diacron-reactive oxygen metabolites(d-ROM), biological antioxidant potential(BAP), and modified ratio of oxidative stress and antioxidant capacity(m-OA) were measured using the Free Radical Analytical System before and 8 wk after induction of therapy with infliximab or adalimumab. The values for oxidative stress were correlated with disease activity and clinical response as determined by the CD activity index(CDAI) at 8 and 54 wk after the therapy.RESULTS: Prior to treatment, d-ROM showed significant correlations with CDAI(r = 0.42, P 0.01). There was a significant negative correlation between m-OA and CDAI before and after treatment(r =-0.48 vs r =-0.42, P 0.01). CDAI and d-ROM had decreased significantly by 8 wk after treatment(CDAI; 223.3 ± 113.2 vs 158.3 ± 73.4, P 0.01, d-ROM; 373 ± 133 vs 312 ± 101, P 0.05). However, neither BAP nor m-OA had changed significantly. In patients who had responded to the treatment at 8 wk, d-ROM, BAP, and m-OA levels before treatment did not differ significantly between patients with and without loss of response.CONCLUSION: Anti-TNF-α therapy decreases oxi-dative stress in patients with CD, but does not alter the production of antioxidants. Dysregulation of antioxidants may be associated with the disease.     

Demethylation of tumor necrosis factor-α converting enzyme promoter associated with high hepatitis B e antigen level in chronic hepatitis B

AIM: To evaluate tumor necrosis factor-α converting enzyme(TACE) methylation status in patients with chronic hepatitis B(CHB).METHODS: Eighty patients with hepatitis B e antigen(HBe Ag)-positive CHB, 80 with HBe Ag-negative CHB, and 40 healthy controls(HCs) were randomly enrolled in this study. Genomic DNA was extracted from peripheral blood mononuclear cells and methylation status of TACE promoter was determined by methylation-specific polymerase chain reaction. The clinical and laboratory parameters were collected.RESULTS: One hundred and thirty of 160 patients with CHB(81.25%) and 38 of 40 HCs(95%) displayed TACE promoter methylation. The difference was significant(χ2 = 4.501, P 0.05). TACE promoter methylation frequency in HBe Ag-positive CHB(58/80, 72.5%) was significantly lower than that in HBe Ag-negative CHB(72/80, 90%; χ2 = 8.041, P 0.01) and HCs(χ2 = 8.438, P 0.01). However, no significant difference was observed in the methylation frequency between HBe Agnegative CHB and HCs(χ2 = 0.873, P 0.05). In the HBe Ag-positive group, TACE methylation frequency was significantly negatively correlated with HBe Ag(r =-0.602, P 0.01), alanine aminotransferase(r =-0.461, P 0.01) and aspartate aminotransferase(r =-0.329, P 0.01). CONCLUSION: Patients with HBe Ag-positive CHB have aberrant demethylation of the TACE promoter, which may potentially serve as a biomarker for HBe Ag seroconversion.