TNF-alpha Gene Promoter Polymorphisms Research Articles

Lack of association between 4 key TNF-alpha promoter polymorphisms and hepatitis C virus infection in a population of Egyptian patients

Introduction: With 170 million chronic hepatitis C virus (HCV) cases worldwide, HCV is considered a major life-threatening pathogen. HCV is a crucial causative of liver cirrhosis and hepatocellular carcinoma. Tumor necrosis factor-alpha (TNF-alpha) is thought to be a mediator in the development of viral hepatitis. Because HCV is epidemic in Egypt, this study aimed to characterize the distribution of TNF-alpha gene promoter polymorphisms and their relation to TNF-alpha expression in HCV patients.
 Methods: Four promoter polymorphisms; −1031T/C, −863C/A, −857C/T, and −308G/A, were studied by restriction fragment length polymorphism in a population of Egyptian HCV patients.
 Results: Compared to healthy subjects, none of these polymorphisms were associated with HCV infection. The wild-type −1031T, −863A, −857C, and −308G alleles were highly prevalent in the studied population. Sequencing the promoter region spanning the four studied polymorphisms in some subjects did not reveal any difference in the nucleotide variance pattern, compared with the TNF-alpha reference sequence. Relative TNF-alpha mRNA expressions in HCV patients and healthy subjects were statistically indifferent.
 Conclusion: Since previous studies confirmed an increase in TNF-alpha level in case of viral infections, this study focuses on mechanisms of post-transcriptional and posttranslational modifications of TNF-alpha gene in HCV patients, which decode the genetic factors linked to HCV infection and severity.

The -863 TNF-α Polymorphism and Primary Open Angle Glaucoma in Egyptians

Growing evidence indicates that TNF-alpha is involved in the pathogenesis of POAG in several ways, primarly by induction of retinal ganglion cells apoptosis and therefore optic nerve degeneration. TNF-alpha and POAG relationship has been studied at the genetic level with variable results in different populations. The transcription rate and the release of the TNF-alpha cytokine have been reported to be affected by polymorphisms in the promoter of the TNF- alpha gene. Polymorphisms at positions -238 and -308 are the most frequent studied. Another polymorphism, at the position -863 in the promoter region, has been less studied, but a homozygous AA allele appears protective in a Chinese population. Our aim was to assess the potential association of -863C/A TNF-alpha gene promoter polymorphisms with POAG in an Egyptian group of subjects. Genotyping of the TNF-alpha (-863) polymorphism was done for 228 POAG patients and 230 control subjects using the PCR-based, Restriction Fragment Length Polymorphism (RFLP) assay. TNF-alpha (-863) A/A genotype was absent in both groups. There was no significant difference between both groups as regards to TNF-α (-863) A allele carriage (6.14 versus 10.43%; p = 0. 099)). Also the genotype TNF-α (-863) C/C and the frequency of the tumor necrosis factor-alpha (-863) C allele did not significantly differ between both groups (93.86 versus 89.57%; p = 0. 099) and 96.93 versus 94.78%; p = 0. 107) respectively. Our data indicated that the TNF-alpha (-863) a allele is not linked with primary open angle glaucoma protection among Egyptian patients.

Association Analysis Between –308G/A and –238G/A TNF-Alpha Gene Promoter Polymorphisms and Insulin Resistance in Mexican Women With Gestational Diabetes Mellitus

BackgroundGestational diabetes mellitus (GDM) is characterized by insulin resistance. It has been described that tumor necrosis factor α (TNF-α) plays a key role in the pathogenesis of insulin resistance; moreover,...

The Value of HLA-DRB1 Shared Epitope, −308 Tumor Necrosis Factor-α Gene Promoter Polymorphism, Rheumatoid Factor, Anti-Citrullinated Peptide Antibodies, and Early Erosions for Predicting Radiological Outcome in Recent-Onset Rheumatoid Arthritis

To study the value of HLA-DRB1 shared epitope (SE), -308 tumor necrosis factor-alpha (TNF-alpha) gene promoter polymorphism, rheumatoid factor (RF), anti-citrullinated peptide antibodies (anti-CCP), and baseline erosions for predicting radiological outcome at 1 year in patients with recent-onset rheumatoid arthritis (RA). Radiological damage was assessed by radiographs at baseline and at 1 year in an inception cohort of 134 RA patients with disease duration<or=1 year at study entry. Radiographs were scored with the modified Sharp/van der Heijde (SvdH) erosion score for hands, wrists, and feet. The predictive value of the variables was studied by multiple linear regression analysis, using immunogenetic factors, baseline SvdH erosion score, and type of treatment during the followup period as independent variables, and SvdH erosion score at 1 year as the dependent variable. The SvdH erosion score increased from the baseline visit to the 1-year visit in 49 patients (36.6%). In multiple linear regression analysis, radiological outcome was significantly predicted by SE homozygosity (beta coefficient 1.75; 95% CI 1.54, 2.96; p=0.005) and baseline SvdH erosion score (beta coefficient 1.56; 95% CI 1.4, 1.71; p<0.001). This model explained 78% of the variability of the dependent variable (R2=0.779). Erosive damage at 1 year in patients with recent-onset RA is significantly influenced by SE homozygosity and the presence of baseline erosions, but not by RF status, anti-CCP status, or -308 TNF-alpha genotype.

Tumor Necrosis Factor-α −308 Genotypes Influence Inflammatory Activity and TNF-α Serum Concentrations in Children with Juvenile Idiopathic Arthritis

Considering the relevance of tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-alpha serum concentrations were associated with TNF-alpha -308 genotypes. Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-alpha gene promoter polymorphisms at position -308 by restriction fragment-length polymorphism. One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the -308 GA/AA genotypes and 76% the -308 GG genotype, similar to findings in controls. Patients with the -308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-alpha levels compared to those with the -308 GG genotype. TNF-alpha -308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

TNF-alpha gene polymorphism and TNF-alpha levels in obese Asian Indians with obstructive sleep apnea

Obstructive sleep apnea (OSA) is emerging as a significant disorder in India. Tumor necrosis factor-alpha (TNFalpha) is an important marker of inflammation. Recent data indicate that inflammation may be an important correlate of OSA. The relationships of OSA with TNFalpha levels and TNFalpha gene promoter polymorphism (-308G/A) have not been investigated in obese Asian Indians with OSA. To look for the correlation if any, between TNFalpha gene promoter polymorphism (-308G/A) in obese Asian Indians with and without OSA and correlation of TNFalpha levels with severity of OSA. We studied 207 obese (BMI>25kg/m(2)) subjects; 104 with OSA and 103 without OSA. Both groups were matched for age, body mass index (BMI) and percentage body fat (%BF). Measurements included anthropometric and biochemical (fasting blood glucose, lipid profile and serum TNFalpha levels) parameters and TNFalpha gene promoter polymorphism (-308G/A). The frequency of '-308A'allele in TNFalpha gene was significantly higher in obese subjects with OSA (28.8%; 60/208), when compared with obese subjects without OSA (12.6%; 26/206, p=0.001). Serum TNFalpha levels were significantly higher in obese subjects with OSA [(3.6+/-0.8)pg/ml], when compared with obese subjects without OSA [(3.3+/-0.6)pg/ml, p=0.009]. Frequency of TNFalpha (-308A) allele and serum TNFalpha level was significantly higher in obese Asian Indians with OSA.

Association of TNF-.ALPHA. Gene Promoter C-857T Polymorphism with Higher Serum LDL Cholesterol Levels and Carotid Plaque Formation in Japanese Patients with Type 2 Diabetes

Little has been known about the role of tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms in metabolic syndrome and atherosclerosis in type 2 diabetes, although TNF-alpha was reported to be involved in these conditions. We examined the association of TNF-alpha gene promoter polymorphisms, G-238A, G-308A, C-857T, C-863A, and T-1031C, with metabolic syndrome and surrogate markers of atherosclerosis in Japanese patients with type 2 diabetes. DNA was obtained from 162 patients and TNF-alpha gene promoter polymorphisms determined by direct sequencing. Allelic frequency of -238A, -308A, -857T, -863A, and -1031C was 0.6%, 2.2%, 11.1%, 16.7%, and 15.7%, respectively. Association of the gene polymorphisms with a number of variables, because of their high frequency, was analyzed in the latter 3 polymorphisms. There were no significant differences in components of metabolic syndrome and variables affecting atherosclerosis, except in case of serum low-density-lipoprotein cholesterol (LDL-C) (111+/-33 vs 125+/-39 mg/dl, p<0.05) between -857C/C and -857(C/T+T/T). In contrast, no significant differences were found in these markers between -863C/C and -863(C/A+A/A) and between -1031T/T and -1031(T/C+C/C). Furthermore, 87% of the patients with -857(C/T+T/T) and 64% with -857C/C had carotid plaques (p<0.05). There was no difference in proportion of patients treated with medications such as statins, fibrates, oral hypoglycemic agents, insulin, or antihypertensive drugs between -857C/C and -857(C/T+T/T). These data imply that TNF-alpha gene polymorphism (C-857T) is likely associated with higher serum LDL-C levels and carotid plaque formation in Japanese patients with type 2 diabetes.

Tumor necrosis factor-alpha gene promoter polymorphism in patients with familial Mediterranean fever

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays an important role on the course of disease in familial Mediterranean fever (FMF). TNF-alpha gene promoter polymorphism may be a marker of susceptibility and severity of FMF. The aim of this study is to evaluate both TNF-alpha/238 and TNF-alpha/308 genotypes and allelic distribution in patients with FMF. Forty-one FMF patients and 43 healthy volunteers were included in the study. Genomic DNA was extracted from EDTA-preserved whole blood of whole series of patients and controls. Polymorphism of TNF-alpha promoter at positions -238 and -308 were detected by using amplification refractory mutation system polymerase chain reaction. TNF-alpha/238 and TNF-alpha/308 genotype distributions and allele frequencies of FMF patients and healthy volunteers were found to be similar. Moreover, there was no association between TNF-alpha/238 and TNF-alpha/308 genotypes and the frequency of acute attacks in FMF. TNF-alpha/238 and TNF-alpha/308 promoter polymorphisms do not seem to be major genetic risk factors for susceptibility to FMF and severity of the disease.

Tumor Necrosis Factor-alpha (TNF-alpha) Gene Promoter Polymorphisms in Patients with Chronic HBV and Spontaneously Recovered among Iranian Population

Purpose: The aim of present study was to examine whether TNF- alpha gene promoter polymorphisms (−308G/A, −857C/T, −863C/A, −1031T/C) are associated with the clearance of HBV infection in chronic HBV patients and spontaneously recovered subjects. Methods: We investigated −308, −857, −863, −1031 TNF-alpha polymorphisms in 100 patients with chronic HBV infection, 100 subjects who had spontaneously recovered from acute HBV infection, and 100 healthy controls. Genomic DNA was obtained from peripheral blood leukocytes by standard phenol-chloroform extraction. The −308G/A, −857C/T, −863A/C, and −1031C/T polymorphisms in the promoter region of TNF-a gene were detected by PCR-RFLP. Results: Our finding have shown that the frequency of −308A, −857C, −863A and −1031C alleles were 0.12, 0.835, 0.21 and 0.245 in chronic HBV patients, respectively; 0.13, 0.775, 0.185 and 0.25 in spontaneous recovered subjects and 0.105, 0.84, 0.13 and 0.16 in healthy controls. As shown in the table below our data suggest no significant difference among chronic HBV patients, spontaneous recovered subjects, and healthy controls considering the four evaluated TNF-alpha promoter polymorphisms (p value > 0.05).Table: Distribution of TNF-Alpha Genotypes in Chronic HBV Patients, Sopontaneously Recovered Subjects and Healthy ControlsConclusions: In contrast to other studies, these findings suggest no association between the TNF-alpha promoter polymorphisms and the development of chronic HBV infection in Iranian population, which probably ethnic differences could lead to different results.

Tumor necrosis factor‐α gene promoter polymorphism is not associated with smoking‐related COPD in Thailand

Susceptibility to COPD is, in part, genetically determined. Tumour necrosis factor (TNF)-alpha gene promoter polymorphisms have been investigated in different populations with inconsistent results. This study aimed to determine the genetic predisposition in Thai smoking-related COPD patients. The polymorphism at position -308 of the TNF-alpha gene promoter was examined in 57 patients with smoking-related COPD, 67 smoker control subjects, and 116 control anonymous blood donors. Genomic DNA from peripheral blood lymphocytes was used for genotypic analysis by polymerase chain reaction with sequence specific primers. TNF-alpha-308*2 allele frequency was not significantly different between the population control subjects and the smoking-related COPD patients (4.7% vs. 7.9%, P= 0.14). This allele frequency was also not significantly different between smokers with and without COPD (7.9% vs. 7.5%, P= 0.46). Although it has been speculated that TNF-alpha might have a causal relationship with COPD, a role for the TNF-alpha gene promoter polymorphism in disease development in Thailand was not demonstrated.

The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population.

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional proinflammatory cytokine, associated with various inflammatory and autoimmune diseases. Elevated TNF-alpha levels in peritoneal fluid have been reported in women with endometriosis, suggesting that TNF-alpha may be involved in the development of endometriosis. In this study, we investigated the possible association between endometriosis and the TNF-alpha gene promoter polymorphisms -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C in a Japanese population. We compared the distribution of the -238G/A, -308G/A, -857C/T, -863C/A and -1031T/C polymorphisms in the promoter region of TNF-alpha in 130 endometriosis cases and 185 controls using PCR-RFLP analysis. The allele frequencies of -238A, -308A, -857T, -863A and -1031C in controls were 2.0%, 1.3%, 19.4%, 17.0% and 18.6%, and in the cases 1.1%, 0.3%, 19.6%, 18.6% and 13.6%, respectively. No significant differences in frequencies were found between the crude endometriosis cases and controls. However, when the endometriosis group was divided into a subgroup of women with stage IV disease only, the frequency of the -1031C allele was significantly lower in this subgroup than controls. The variability of the -1031T/C polymorphism of the TNF-alpha gene may be associated with susceptibility to (AUTHOR: as meant?) endometriosis.

Association of TNF-alpha gene promoter polymorphism with narcolepsy-cataplexy in Koreans

Association of TNF-alpha gene promoter polymorphism with narcolepsy-cataplexy in Koreans

Association of -238G/A polymorphism of tumor necrosis factor-alpha gene promoter region with outcomes of hepatitis B virus infection in Chinese Han population.

To clarify whether -238G/A polymorphism of tumor necrosis factor-alpha (TNF-alpha) gene promoter region was associated with outcomes of hepatitis B virus (HBV) infection in Han population of northern China, and to analyze the gene-environment interaction between -238G/A polymorphism and cigarette smoking or alcohol consumption. A case-control study was conducted to analyze the association of TNF-alpha gene promoter polymorphism with HBV infection outcomes. A total of 207 patients with chronic hepatitis B (HB) and 148 cases of self-limited HBV infection from Ditan Hospital and Shunyi District Hospital in Beijing, respectively were recruited. History of smoking and alcohol drinking was inquired by a questionnaire. The -238G/A polymorphism of TNF-alpha gene promoter was genotyped by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). The frequencies of GG and GA genotypes were 98.07% and 1.93% in chronic HB patients and 93.24% and 6.76% in self-limited HBV infection individuals, respectively (chi(2)=5.30, P=0.02). The frequency of G allele was significantly higher in patients with chronic HB that in individuals with self-limited HBV infection (99.03% vs 96.62%, chi(2)=5.20, P=0.02). Only modestly increased risk of onset of chronic HB was found in smokers (OR=1.40, 95% CI: 0.87-2.28, P=0.14) and drinkers (OR=1.26, 95%CI: 0.78-2.05, P=0.32). There was a positive interaction between genotype GG and cigarette smoking with an interaction index (II) of 2.95, or alcohol consumption with an II of 1.64. The -238G/A polymorphism of TNF-alpha gene promoter region is independently associated with different outcomes of HBV infection.

Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis.

To study tumor necrosis factor alpha (TNFalpha) -308 gene promoter polymorphism and circulating levels of TNFalpha and soluble TNF receptor type I (sTNFRI) in rheumatoid arthritis (RA) patients with and without reactive amyloidosis. In a retrospective study, we examined 55 RA patients with biopsy-proven reactive amyloidosis and 55 control RA patients without amyloidosis (matched for age, sex, rheumatoid factor titer, and RA duration). Inflammatory activity was assessed by measuring the erythrocyte sedimentation rate and C-reactive protein level. TNFalpha gene promoter polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine and receptor levels were measured by enzyme-linked immunoassays. Patients with RA and amyloidosis had significantly higher TNFalpha and sTNFRI levels than did the control RA patients. The increased circulating levels of TNFalpha correlated with interleukin-18 levels, but not with the serum amyloid A protein levels or with TNFalpha -308 gene promoter polymorphism (reported to be associated with high TNFalpha levels and certain disease susceptibilities). In the patients with RA and amyloidosis, those with anemia had significantly higher TNFalpha and sTNFRI levels than did those without anemia, and circulating TNFalpha and sTNFRI levels correlated negatively with hemoglobin concentrations. In the patients with RA and amyloidosis, those with nephropathy had significantly higher TNFalpha and sTNFRI levels than did those without nephropathy; in patients with isolated proteinuria (but no creatinine elevation) the TNFalpha level was also significantly increased, indicating that the TNFalpha elevation was not merely a consequence of impaired renal function. This study shows that circulating levels of TNFalpha and sTNFRI are significantly increased in RA patients with amyloidosis as compared with control RA patients without amyloidosis and that the increased levels may be implicated in the pathogenesis of certain disease manifestations, including anemia of chronic disease and renal pathology in reactive amyloidosis.

Lack of association of tumor necrosis factor alpha gene polymorphism in patients with rheumatoid arthritis in central Taiwan.

The aim of this study was to investigate the association of tumor necrosis factor alpha (TNFalpha) gene promoter polymorphisms in Chinese patients with rheumatoid arthritis (RA) in central Taiwan. A total of 106 RA patients and 253 normal controls were studied. Polymerase chain reaction (PCR)-based restriction analysis was used to identify A/G polymorphism at position 308 in the promoter region of the TNFalpha, which is located at 6q21.3. For the genotype of TNFalpha-308 polymorphism, there was no statistically significant difference between RA patients and normal controls (Fisher's exact test, P=0.82). Additionally, no statistical association in the distribution of TNFalpha-308 polymorphism between rheumatoid factor (RF)-positive and -negative patients was noted. The lack of an association of TNFalpha-308 polymorphism with RA and RF in our study implies that TNFalpha-308 polymorphism cannot serve as a candidate gene marker for screening RA patients in Taiwan.

Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus.

The role of host genetic factors in chronic hepatitis B virus (HBV) infection is not fully understood. We studied the influence of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) gene promoter polymorphisms on disease progression in HBV carriers. The sample population included 213 Japanese HBV carriers and 52 healthy volunteers. Of 213 HBV carriers, 66 were considered to be asymptomatic carriers based on the sustained normalization of serum ALT together with seropositivity for the antibody to hepatitis B e antigen (anti-HBe), and 147 were found to have chronic progressive liver disease including cirrhosis. Five biallelic polymorphisms in the TNF-alpha gene promoter and three biallelic polymorphisms in the IL-10 gene promoter were analyzed by polymerase chain reaction in combination with direct sequencing or restriction fragment length polymorphism assay. Allelic distributions of both gene promoters were not significantly different between HBV carriers and healthy volunteers. In HBV carriers, the TNF-alpha gene promoter polymorphisms were not linked to disease progression. In contrast, allelic frequencies of T and A at positions -819 and -592, respectively, in the IL-10 gene promoter, as well as the frequencies of ATA haplotype at positions -1082/-819/-592 (which is characterized with low capacity for IL-10 production), were significantly higher in asymptomatic carriers than in patients with chronic progressive liver disease. Even after adjusting for individuals positive for anti-HBe, such a relationship could be found between the two groups. In chronic HBV infection, inheritance of the IL-10 gene promoter polymorphisms is involved in a host genetic factor that is relevant to disease progression.

The Role of TNFalpha Gene Promoter Polymorphism in the Development of Coal Workers' Pneumoconiosis

The Role of TNFalpha Gene Promoter Polymorphism in the Development of Coal Workers' Pneumoconiosis

Tumor necrosis factor genomic polymorphism in Spanish IGA deficiency patients.

Selective IgA deficiency (IgAD) is the most common form of primary immunodeficiency. Its association with genes within the major histocompatibility complex (MHC) has been repeatedly reported. Recently the susceptibility gene has been located in the class III region, around the tumor necrosis factor (TNF) cluster. In this study we have examined IgAD association with TNF-alpha gene promoter polymorphisms and TNFa and b microsatellites. No significant association was found with the former polymorphisms and the observed associations with TNFa2 allele and haplotypes TNFa2b1 and TNFa2b3 were proven to be secondary to their occurrence on the B14-DR1 and B8-DR3 haplotypes, previously reported to be associated with susceptibility to IgAD. However, a primary negative (protective) association was found between the TNFa10 allele and IgAD.

Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid.

Tumor necrosis factor alpha (TNF-alpha) may play a central role in the disease pathogenesis which occurs as a consequence of chlamydial infection. To investigate the importance of TNF-alpha gene promoter polymorphisms and TNF-alpha levels in tear fluid in scarring trachoma, a large matched-pair case-control study was performed in The Gambia. The -308A allele was present in a higher proportion of patients (28.4%) than controls (18.4%), with an increasing association for homozygotes (chi2 for trend, P = 0.032; allele frequency, 0.163 in patients and 0.099 in controls; chi2, P = 0.025). For the -238A allele, the association was similar but not significant. The disease association was highly significant when the number of either -308A or -238A sites in an individual was considered (P = 0.003). TNF-alpha promoter alleles are tightly linked to some HLA class I and II alleles, but multivariate analysis confirmed that the disease associations were independent of HLA, although a class I allele, A*6802, is also associated with disease. TNF-alpha was more frequently detected in tear samples from patients (27.6%) than from controls (15.9%), increasingly so for higher levels of detectable TNF-alpha (P = 0.015). Among patients, detectable TNF-alpha in tears was highly associated with the presence of ocular chlamydial infection (P < 0.001). The results indicate that TNF-alpha plays a major role in the tissue damage and scarring which occurs as a consequence of Chlamydia trachomatis infection.