TNF-α Promoter Polymorphisms Research Articles

Meta-analysis: the relationship between TNF-alpha polymorphisms and susceptibility to primary biliary cirrhosis.

To investigate the possible influence of TNF-α gene promoter polymorphisms in conferring a predisposition to PBC patients. We performed a meta-analysis of nine articles searched from PubMed up to July 2010 that investigated the association between two TNF-α polymorphisms (-308 and -238) and PBC. The data showed no significant association between TNF-α-308, -238 gene polymorphisms and the susceptibility to PBC in the global group (OR=0.95, 95%CI=0.80-1.13, p=0.55; OR=1.00, 95%CI=0.65-1.55, p=0.99, respectively). Stratified by sub-groups (European, American, Asian), TNF -308 minor allele, but not -238, was found to be a protective factor in the European population (OR= 0.81, 95%CI=0.67-0.99, p=0.04; OR=0.99, 95%CI=0.55-1.77, p=0.97, respectively). Moreover, no significant difference was observed between TNF-α-308 alleles and PBC when stratified by histological stages (stages I-II, OR=0.68, 95%CI=0.32-1.48, p=0.33; stages III-IV, OR=0.69, 95%CI=0.41-1.15, p=0.15). TNF-α promoter polymorphisms might not be associated with PBC risk. However, studies with larger population of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.

The role of TNF-α and TNF-β gene polymorphism in the pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder of unknown etiology that affects the synovial membrane of multiple joints. The clinical presentation of RA may vary from mild to severe with excessive erosions of periarticular bone leading to the loss of functional capacity. Both genetic and environmental factors are important in the development of this disorder. The genetic contribution to susceptibility for RA is underlined by a three-to four-fold higher concordance percentage for clinically expressed disease in monozygotic twins compared to dizygotic twins. The severity and long term outcome of RA have also been related to various genetic factors. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, is involved in the pathogenesis of a variety of autoimmune disorders, including RA. A large number of studies have been undertaken to determine the role of TNF-α promoter polymorphisms in the pathogenesis of RA. On the other hand few attempts have been made to identify the association between TNF-α (lymphotoxin-alfa) polymorphism and RA. In this narrative review of published literature, an attempt has been made to determine the association between TNF-α promoter polymorphisms at positions –308, –238, –489, –857, –863 and TNF-β at +252 with respect to susceptibility to and severity of RA, as well as response to drug therapy. In spite of intra-and inter-ethnic variations, analysis of data suggests a significant role of TNF-α/TNF-β polymorphisms in determining the susceptibility/severity of RA and responsiveness to anti-TNF drug therapy. The TNF gene polymorphisms may be an interesting target for novel strategies to prevent RA and/or in its early treatment. Further studies using larger samples are needed to pinpoint the regulatory polymorphisms or haplotypes and their effects on the development of certain manifestations in RA.

The role of TNF-α and TNF-β gene polymorphism in the pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder of unknown etiology that affects the synovial membrane of multiple joints. The clinical presentation of RA may vary from mild to severe with excessive erosions of periarticular bone leading to the loss of functional capacity. Both genetic and environmental factors are important in the development of this disorder. The genetic contribution to susceptibility for RA is underlined by a three-to four-fold higher concordance percentage for clinically expressed disease in monozygotic twins compared to dizygotic twins. The severity and long term outcome of RA have also been related to various genetic factors. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, is involved in the pathogenesis of a variety of autoimmune disorders, including RA. A large number of studies have been undertaken to determine the role of TNF-α promoter polymorphisms in the pathogenesis of RA. On the other hand few attempts have been made to identify the association between TNF-α (lymphotoxin-alfa) polymorphism and RA. In this narrative review of published literature, an attempt has been made to determine the association between TNF-α promoter polymorphisms at positions –308, –238, –489, –857, –863 and TNF-β at +252 with respect to susceptibility to and severity of RA, as well as response to drug therapy. In spite of intra-and inter-ethnic variations, analysis of data suggests a significant role of TNF-α/TNF-β polymorphisms in determining the susceptibility/severity of RA and responsiveness to anti-TNF drug therapy. The TNF gene polymorphisms may be an interesting target for novel strategies to prevent RA and/or in its early treatment. Further studies using larger samples are needed to pinpoint the regulatory polymorphisms or haplotypes and their effects on the development of certain manifestations in RA.

Promoter polymorphisms of the TNF a (-308 G/A) and IL-6 (-174G/C) genes predict therapeutic response to etanercept

Event Abstract Back to Event Promoter polymorphisms of the TNF α (-308 G/A) and IL-6 (-174G/C) genes predict therapeutic response to etanercept Ivan Jančić1*, Nevena Arsenović-Ranin1, Mirjana Šefik-Bukilica2, Slađana Živojinović2, Nemanja Damjanov2, Vesna Spasovski3, Sanja Srzentić3, Biljana Stanković3 and Sonja Pavlović3 1 Faculty of Pharmacy, University og Belgrade, Serbia 2 Institute of Rheumatology, Serbia 3 Institute of Molecular Genetics and Genetic Engineering, Serbia The aim of the study was to explore putative influence of - 308 G/A TNFα and –174 G/C IL-6 promoter polymorphisms (releated to TNFα and IL-6 level) on the therapeutic response to etanercept, a TNFα blocker, in patients with rheumathoid arthritis (RA). 73 patients suffering from active RA were examined at the begining of etanercept treatment and 6- and 12-months following the begining of the treatment. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for –308 G/A TNFα and –174 G/C IL-6 gene polymorphisms by the PCR-RFLP method, and influence of the genotype to clinical response to etanercept was assessed. Association between –308 G/A TNFα polymorphism and a response to etanercept after 6 and 12 months of therapy was not found. After 12 months the percentage of responders (patients who had DAS28 improvement > 1.2) was significantly increased in patients with the –174 GG IL-6 genotype (95.7 %) compared with those with the –174 GC IL-6 (75.6 %) and –174 CC IL-6 (44.4 %) genotype (p = 0.006). The best responders after 12 months were patients with –308 GG TNFα/–174 GG IL-6 genotype combination compared to the other genotype combinations (p = 0.022). The patients with RA exhibiting –308 GG TNFα/–174 GG IL-6 genotype respond better to etanercept than patients with other genotypes examined. This finding suggests that this polymorphism combination should be considered as a genetic marker of responsiveness to TNFα blockers in RA. Keywords: - 308 G/A TNFα promoter polymorphism, –174 G/C IL-6 promoter polymorphism, ra, etanercept, das28 responders Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Jančić I, Arsenović-Ranin N, Šefik-Bukilica M, Živojinović S, Damjanov N, Spasovski V, Srzentić S, Stanković B and Pavlović S (2013). Promoter polymorphisms of the TNF α (-308 G/A) and IL-6 (-174G/C) genes predict therapeutic response to etanercept. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00173 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mr. Ivan Jančić, Faculty of Pharmacy, University og Belgrade, Belgrade, Serbia, ijancic@pharmacy.bg.ac.rs Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Ivan Jančić Nevena Arsenović-Ranin Mirjana Šefik-Bukilica Slađana Živojinović Nemanja Damjanov Vesna Spasovski Sanja Srzentić Biljana Stanković Sonja Pavlović Google Ivan Jančić Nevena Arsenović-Ranin Mirjana Šefik-Bukilica Slađana Živojinović Nemanja Damjanov Vesna Spasovski Sanja Srzentić Biljana Stanković Sonja Pavlović Google Scholar Ivan Jančić Nevena Arsenović-Ranin Mirjana Šefik-Bukilica Slađana Živojinović Nemanja Damjanov Vesna Spasovski Sanja Srzentić Biljana Stanković Sonja Pavlović PubMed Ivan Jančić Nevena Arsenović-Ranin Mirjana Šefik-Bukilica Slađana Živojinović Nemanja Damjanov Vesna Spasovski Sanja Srzentić Biljana Stanković Sonja Pavlović Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo

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.

Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level

Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of Plasmodium falciparum mediated malaria. We previously published genetic association of TLR4 non-synonymous and TNF-α promoter polymorphisms with P.falciparum blood infection level and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms, (ii) reconstructing gene-gene interactions among candidate TLRs and cytokine loci, (iii) exploring genetic and functional impact of epistatic models and (iv) providing mechanistic insights into functionality of disease-associated regulatory polymorphisms. Our data revealed that carriage of AA (P = 0.0001) and AC (P = 0.01) genotypes of IL12B 3′UTR polymorphism was associated with a significant increase of mean log-parasitemia relative to rare homozygous genotype CC. Presence of IL12B+1188 polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype. Elevation of genetic risk in two-component models compared to the corresponding single locus and reduction of IL12B (2.2 fold) and lymphotoxin-α (1.7 fold) expressions in patients'peripheral-blood-mononuclear-cells under TLR4Thr399Ile risk genotype background substantiated the role of Multifactor Dimensionality Reduction derived models. Marked reduction of promoter activity of TNF-α risk haplotype (C-C-G-G) compared to wild-type haplotype (T-C-G-G) with (84%) and without (78%) LPS stimulation and the loss of binding of transcription factors detected in-silico supported a causal role of TNF-1031. Significantly lower expression of IL12B+1188 AA (5 fold) and AC (9 fold) genotypes compared to CC and under-representation (P = 0.0048) of allele A in transcripts of patients' PBMCs suggested an Allele-Expression-Imbalance. Allele (A+1188C) dependent differential stability (2 fold) of IL12B-transcripts upon actinomycin-D treatment and observed structural modulation (P = 0.013) of RNA-ensemble were the plausible explanations for AEI. In conclusion, our data provides functional support to the hypothesis that de-regulated receptor-cytokine axis of innate immune pathway influences blood infection level in P. falciparum malaria.

Lack of association between TNF-α promoter polymorphisms and multiple myeloma: A meta-analysis

Results of available literatures, which concerned the association between TNF-α promoter −238/−308 gene polymorphisms and multiple myeloma (MM), are of great controversy. A review was performed in studies reporting on the association between them. Odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the association. The pooled ORs indicated that there was no association between TNF-α −238/−308 polymorphisms and MM susceptibility in overall population. Sub-group analysis also confirmed that no evidence supported the relevance of TNF-α promoter −238/−308 gene polymorphisms with MM. Studies with large sample size and multi-ethnics may be needed to further explore the association between them.

Association of -308 TNF-alpha promoter polymorphism with viral load and CD4 T-helper cell apoptosis in HIV-1 infected black South Africans

Objective. To determine whether the -308 TNF-α promoter polymorphism is associated with markers of HIV progression in the South African population.
 
 Methods. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the -308 TNF-α polymorphism in 75 patients and 76 healthy controls. Serum TNF-α concentrations were measured using ELISA in each cohort. CD4+ T cell apoptosis and HIV-1 RNA viral load were determined using Annexin-V-FITC assay and Nuclisens Easy Q HIV-1 assay respectively. CD4 + T cell counts were measured flow cytometrically.
 
 Results. The frequency of -308 G allele was similar in the HIV-1 and control cohorts. The -308GG genotype was associated with lower TNF-α concentrations and markers of increased HIV progression indicated by higher TH lymphocyte apoptosis, lower TH lymphocyte count and higher plasma viral load, irrespective of treatment.
 
 Conclusion. The presence of the TNF-α -308 G allele in HIV-1 patients may be associated with increased risk of HIV-1 progression. Further research is required to investigate the nature of this association. 
 
 S Afr J HIV Med 2012;13(2):72-77.

TNF-α and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk

Although the implication of genetic factors in cervical cancer development remains to be elucidated, accumulative epidemiological evidence suggests that polymorphisms of cytokine genes may be involved in the etiology of cervical carcinoma. Tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) are two multifunctional cytokines implicated in inflammation, immunity, and cellular organization, and were proposed to play important roles in cancer biology. In order to determine whether IL-10 -1082 (G/A) and TNF-α -238 (G/A) and -308 (G/A) polymorphisms are associated with susceptibility to cervical cancer, a case-control study of 122 cancer patients and 176 healthy controls was conducted. Cervical samples were genotyped for both TNF-α polymorphisms by PCR-RFLP assay. SNP-1082 from IL-10 gene was genotyped using pyrosequencing technology. The association between cervical cancer risk and the studied SNPs was evaluated by logistic regression. Under univariate analysis, none of these polymorphisms appeared associated with susceptibility of cervical cancer development or HPV infection. However, individuals carrying heterozygous genotype for TNF-α -238 polymorphism seem to be at lower risk for cervical cancer development, with borderline significance (OR = 0.42, P = 0.069), as well as those carrying heterozygous genotypes for IL-10 and TNF-α -238 (OR = 0.40, P = 0.08). In conclusion, these results suggest a potential effect of TNF-α -238 G/A in the reduction of cervical cancer risk in Argentine women, but not TNF-α -308 or IL-10. Larger studies are needed to fully understand the genetic predisposition for the development of cervical cancer.

Association of TNF-α and Fas gene promoter polymorphism with the risk of Kashin–Beck disease in Northwest Chinese population

The objective of this study is to investigate the relationship between single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor-α (TNF-α) and Fas genes and Kashin-Beck disease (KBD) in Shaanxi province, Northwest in China. Blood samples of 388 residents were collected from 14 KBD villages in Linyou and Yongshou counties, Shaanxi, Northern of China. One hundred eighty-six cases with KBD and 202 cases of health in KBD areas were diagnosed by "Diagnosis Criterion of Kashin-Beck disease in China (WS/T207- 2010)". The TNF-α -308G/A, TNF-α -238G/A, and Fas -670A/G SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in combination with sequence analysis in KBD and healthy control groups. The genotypes and allele frequencies distribution of these SNPs were then analyzed. TNF-α -308A allele frequency in KBD patients were significantly higher than that in healthy controls. Although TNF-α -238 genotypes and allele frequencies were not significantly different between KBD patients and the healthy controls, GA genotype and A allele frequency in KBD patients were higher than those in healthy controls. The TNF-α -308G/A SNPs were associated with the susceptibility of KBD.

TNF-α promoter polymorphism: a factor contributing to the different immunological and clinical phenotypes in Japanese encephalitis

BackgroundMore than three billion populations are living under the threat of Japanese encephalitis in South East Asian (SEA) countries including India. The pathogenesis of this disease is not clearly understood and is probably attributed to genomic variations in viral strains as well as the host genetic makeup. The present study is to determine the role of polymorphism of TNF-alpha promoter regions at positions -238G/A, -308G/A, -857C/T and -863C/A in the severity of Japanese encephalitis patients.MethodsTotal of 142 patients including 66 encephalitis case (IgM/RT-PCR positive), 16 fever cases (IgM positive) without encephalitis and 60 apparently healthy individuals (IgG positive) were included in the study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using site specific restriction enzymes were implemented for polymorphism study of TNF alpha promoter.ResultsFollowing the analysis of the digestion patterns of four polymorphic sites of the TNF- alpha promoter region, a significant association was observed between the allele -308A and -863C with the patients of Japanese encephalitis.ConclusionsTNF- alpha 308 G/A has been shown to be associated with elevated TNF- alpha transcriptional activity. On the other hand, polymorphism at position -863C/A in the promoter region has been reported to be associated with reduced TNF- alpha promoter activity and lower plasma TNF levels. As per the literature search, this is the first study to identify the role of TNF- alpha promoter in JE infection. Our results show that subjects with - 308A and -863C alleles are more vulnerable to the severe form of JE infection.

Associations between TNF-α, IL-6 and IL-10 Promoter Polymorphisms and Mortality in Severe Sepsis

Aims: To determine whether an association exists between TNF-α 308 A/G, IL-6 174 G/C, and IL-10-1082 A/G promoter polymorphisms and the corresponding systemic cytokine concentrations and outcome in patients suffering from sepsis. Place and Duration of Study: The study was performed in the Intensive Care Unit (ICU)

Role of Tumor Necrosis Factor-α Promoter Polymorphism and Insulin Resistance in the Development of Non-alcoholic Fatty Liver Disease in Obese Children

Purpose: Tumor necrosis factor-α (TNF-α) polymorphism has been suggested to play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in obese adults, and known to be a mediator of insulin resistance. In this study, we evaluated the role of TNF-α promoter polymorphisms and insulin resistance in the development of NAFLD in obese children. Methods: A total of 111 obese children (M:F=74:37; mean age, 11.1±2.0 yrs) were included. The children were divided into 3 groups: controls (group I, n=61), children with simple steatosis (group II, n=17), and children with non-alcoholic steatohepatitis (group III, n=33). Serum TNF-α levels, homeostasis model assessment of insulin resistance (HOMA-IR), and TNF-α -308 and -238 polymorphisms were evaluated. Results: There were no differences in TNF-α polymorphism at the -308 or the -238 loci between group I and group II + III (p=0.134 and p=0.133). The medians of HOMA-IR were significantly different between group I and group II + III (p=0.001), with significant difference between group II and group III (p=0.007). No difference was observed in the HOMA-IR among the genotypes at the -308 locus (p=0.061) or the -238 locus (p=0.207) in obese children. Conclusion: TNF-α promoter polymorphisms at the -308 and -238 loci were not significantly associated with the development of NAFLD in children; nevertheless, insulin resistance remains a likely essential factor in the pathogenesis of NAFLD in obese children, especially in the progression to NASH. (Pediatr Gastroenterol Hepatol Nutr 2012; 15: 44-51)

Abstract P106: Polymorphisms in Candidate Genes and Early Atherosclerosis: A Study of 115 Autopsy Cases of Young Adults

Atherosclerosis, a major cause of death, is a complex disease, involving both genetic and environmental factors. Chronic inflammation plays a central role in its pathogenesis; however, the influence of genetic variations on early development of atherosclerosis has been poorly investigated. We examined the relationship of five common single-nucleotide polymorphisms (SNPs) with atherosclerotic severity in the anterior descendent coronary artery (DA) in 115 consecutive individuals under 30 years autopsied at the Legal Medical Institute of Rio de Janeiro. Histological sections were stained with hematoxilin-eosin and classified for atherosclerosis lesion accordingly to the American Heart Association. DNA was extracted and genotyped for SNPs in the angiotensin conversion enzyme, tumoral necrosis factor-alpha (−308G/A and −238 G/A), interferon-gama (+874 A/T), and metalloproteinase-9 (−1562 C/T) genes by automatic sequencing. Fire weapon lesion was the major causa mortis (72%). Population mean age was 26 years, 100 male and 15 female; 35% were slims, 58% regular weight and 7% obese; 22% white, 51% non-white, and 17% blacks. Only 2 subjects had normal DA histology, while 17 presented level II lesions, 74 level III, 7 level IV, 14 level V. and 1 level VI. 49 individuals presented genotype DD, related to high serum levels of ECA, while 18 were II (related with low ECA levels) and 48 DI (allele frequencies of D = 0,635; I = 0,365). For TNF-α promoter polymorphisms (where allele A is associated with high TNF-α level), 59 presented genotype GG, 21 GA, and 8 AA at position -308 (G = 0,790; A = 0,210), while 84 were GG, 3 GA, and 2 AA at position -238 (G = 0,961; A = 0,039). The allele T at position +874 of INF-γ (related to high INF-γ levels) was present in 45 subjects, while for MMP-9 SNP 49 individuals presented genotype CC, 14 CT, and 3 TT (C = 0,848; T = 0,152). In conclusion, we observed a high prevalence of early atherosclerotic lesions (level III) in young adults, with high prevalence of DD genotype, associated with high ECA serum levels.

Association of tumor necrosis factor-α (TNF-α) promoter polymorphisms with overweight/obesity in a Korean population

Obesity is characterized by the activation of an inflammatory process leading to an increase in proinflammatory cytokines and adipokines. This study was designed to investigate the genetic association between tumor necrosis factor-α (TNF-α) polymorphisms and the risk of obesity in the Korean population. Three single nucleotide polymorphisms [G-238A (rs361525), C-857T (rs1799724), and C-863A (rs1800630)] in the promoter region of TNF-α gene were analyzed in 123 control [body mass index (BMI) between 18 and 23] and 208 overweight/obese (BMI≥23) subjects. The mean values of BMI in the control and overweight/obese groups were 21.1±1.4 and 25.4±1.8, respectively. Of the three SNPs, G-238A presented a significant association with overweight/obesity in the codominant model; the frequency of the G/G genotype in the overweight/obese group was 9.3% higher than that in the control group (P=0.0046). When control and overweight/obesity subjects were combined together and analyzed, the level of high-density lipoprotein (HDL) was significantly higher in the C-857T C/C type SNP (P<0.05). The results of this study suggest that the G allele of G-238A in TNF-α gene may be a risk factor for overweight/obesity in the Korean population and that the C allele of C-857T may be an protective factor in relation to the HDL level in the general Korean population.

Association of −308 TNF-α promoter polymorphism with clinical aggressiveness in patients with head and neck squamous cell carcinoma

Genetic polymorphisms in the promoter region of the tumour necrosis factor-α (TNF-α) gene are involved in the regulation of the expression levels of its cytokine. Besides, these polymorphisms have been associated with the clinical behaviour of cancer. We investigated the -308 promoter region polymorphisms of the TNF-α gene and its association with the clinicopathological factors of a head and neck squamous cell carcinoma (HNSCC) sample. Furthermore, we analysed the impact of all the variables on the overall survival of patients. A sample of HNSCC (n=89) was evaluated. Clinicopathological factors and overall survival data were gathered. The TNF-α gene was analysed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data analyses were performed by using bivariate and multivariate statistical tests. Significance was set at p<0.05. HNSCC subjects carrying the A allele (GA/AA) exhibited associations with poor performance status (OR=2.82, p=0.039), lesions located on posterior areas (OR=4.02, p=0.002), and large-size tumours (OR=2.91, p=0.015). Subjects carrying only AA genotype exhibited association with poor performance status (OR=6.667, p=0.007). A worse overall survival was noted in subjects with large tumours (OR=4.87, p=0.005) and locoregional metastatic disease (OR=2.50, p=0.018). Our data suggests that the presence of the A allele/AA haplotype in HNSCC individuals might contribute to the higher clinical aggressiveness of malignant disease.

A meta-analysis on the association between three promoter variants of TNF-α and Crohn’s disease

Tumor necrosis factor-alpha (TNF-α) has been regarded as a candidate gene for Crohn's disease (CD) based on its inflammatory function in immune reaction and the clinical effectiveness of anti-TNF-α therapy. However, studies to date have reported inconsistent findings for the association between TNF-α and CD. The PubMed, EMBASE, and Medline databases were systematically reviewed from all English language publications up to April, 2011. A total of twenty-nine studies concerning the association between CD and the TNF-α promoter polymorphisms of -308G/A, -857C/T and -238G/A were identified, among of them only twenty-three studies match the inclusion criteria (including 3,843 cases and 6,260 controls) and were selected for the statistical test. We found that neither the G allele of -308G/A (OR 1.02, 95% CI 0.87-1.19, P = 0.84), C allele of -857C/T (OR 0.97, 95% CI 0.86-1.09, P = 0.57) and G allele of -238G/A (OR 0.91, 95% CI 0.70-1.18, P = 0.48), and nor their GG (OR 1.05, 95% CI 0.88-1.25, P = 0.59), CC (OR 0.98, 95% CI 0.86-1.12, P = 0.76) and GG (OR 0.92, 95% CI 0.70-1.21, P = 0.55) genotypes were associated with CD susceptibility, respectively. Our meta-analysis demonstrates that three promoter polymorphisms of TNF-α above may not confer susceptibility to CD.

Functional study of TNF-α promoter polymorphisms : literature review and meta-analysis

The functional consequences of TNF-α promoter SNPs are still controversial and, to date, the functional consequences of TNF-α haplotype combinations in healthy subjects have not been assessed. In order to assess functional consequences of each TNF-α polymorphism and of their haplotype combination, TNF-α expression and secretion by LPS-stimulated monocytes from 50 healthy subjects were assessed. Monocytes were isolated and cultured for four hours, after 100 ng/mL LPS stimulation. mRNA expression was quantified using the real-time polymerase chain reaction, and TNF-α levels were measured by enzyme-linked immunosorbent assay. Each subject was genotyped for TNF-α -857 C/T, -238 G/A, -308 G/A polymorphisms. In order to confirm definitively the functional consequences of these TNF-α polymorphisms, we then performed a systematic review of the literature for TNF-α SNPs, and then a meta-analysis of the functional studies of the TNF-α -308 G/A SNP. No association between TNF-α mRNA or protein level expression, and TNF-α -238G/A, -308G/A, -857C/T polymorphisms, studied either independently or in haplotype combinations, was revealed. Using a meta-analysis for the TNF-α -308 G/A polymorphism, we confirmed the absence of any association between TNF-α mRNA and protein levels, and TNF-α -308 G/A genotypes. This study and meta-analysis of the literature confirmed the absence of any functional consequences of the TNF-α -308G/A promoter polymorphism, either alone, or in various haplotype combinations in healthy subjects.

Association of polymorphisms in the promoter regions of TNF-α (−308) with susceptibility to hepatitis E virus and TNF-α (−1031) and IFN-γ (+874) genes with clinical outcome of hepatitis E infection in India

Hepatitis E virus (HEV) is the predominant cause of acute viral hepatitis (AVH-E) and acute liver failure (ALF-E) among adults from developing countries. Pathogenesis of hepatitis E is poorly understood. Earlier, we showed association of elevated serum levels of TNF-α, IFN-γ, and IL-12 with ALF-E. The role of TNF-α and IFN-γ gene promoter polymorphisms with disease severity was investigated. The study population included 374 anti-HEV negative apparently healthy controls, 136 subclinical hepatitis E, 353 AVH-E, and 25 ALF-E patients. Polymorphisms at promoter regions of TNF-α-308G/A, TNF-α-1031T/C, and IFN-γ+874T/A were investigated employing allelic discrimination/SNaPshot™ methods. ALF-E patients were younger with significantly higher ALT levels when compared to other categories. Genotype TNF-α-308AA frequency was significantly higher among subclinical and clinical hepatitis E than the controls (p=0.03, 0.0007). No significant difference was observed among AVH-E/ALF-E groups. The -308A allele was significantly higher in HEV-infected individuals; fatal ALF patients showed higher frequency than the recovered (p=0.024). TNF-α-1031CC, IFN-γ+874TT, and IFN-γ+874TA genotypes were significantly associated with clinical disease. With respect to the controls, genotype+874TA was more frequent in subclinical infection (p=0.005) while+874AA frequency was lower in the AVH-E category (p=0.003). The data reveal association of TNF-α-308AA genotype with susceptibility to HEV and that of TNF-α-1031CC and IFN-γ+874TT and TA with clinical disease, irrespective of the outcome. Higher -308A allele frequency was associated with susceptibility to HEV and the fatal outcome of ALF-E.

Association between TNF-α promoter G-308A and G-238A polymorphisms and obesity

Tumor necrosis factor-α (TNF-α), an adipokine, is produced in adipocytes, and the elevation of its levels has been linked to obesity and insulin resistance in some population. In this study the relationship between TNF-α promoter gene polymorphism and obesity in an Iranian population has been studied. Subjects were randomly selected from Tehran Cohort Lipid and Glucose Study. Adult participants placed in three groups according to their body mass index (BMI): BMI < 25, 25 ≤ BMI < 30, BMI ≥ 30 and under-18 subjects placed in two groups, under 85th percentile BMI and above 85th percentile. Finally, 244 persons were selected for G-308A and G-238A polymorphisms analysis. The FBS, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, cholesterol levels and blood pressure and HOMA of all subjects were measured. The polymorphism −308 and −238 were revealed by restriction fragment length polymorphism (RFLP; NCOI and MSPI) after the promoter site was amplified by PCR. The allele frequency of TNF-α polymorphism was in the Hardy–Weinberg equilibrium. There was no relation between BMI and the frequency of this allele. The fact that there is no association between G-308A and G-238A TNF-α promoter polymorphisms and obesity probably shows that it is not an important risk factor for obesity and consequently for cardiovascular disease.