TNF-alpha Promoter Polymorphisms Research Articles

Role of Tumor Necrosis Factor alpha promoter polymorphisms in interferon related side effects in chronic hepatitis B patients under interferon alpha 2b treatment

Objective(s). Interferon alpha therapy is associated with series of adverse effects leading premature discontinuation of treatment. Here we aimed to determine the effects of Tumor necrosis alpha promoter polymorphisms on interferon related side effects during interferon alpha 2b treatment in chronic hepatitis B patients
 Material and Method(s). This observational study enrolled 50 chronic hepatitis B patients, who were treated with interferon alpha 2b 10 tiw plus lamivudine 100mg/day at Selçuk University Meram Medical Faculty Department of Infectious Diseases and Clinical Bacteriology between 2006-2007. Patients were followed-up with complete blood count, transaminases and amylase monthly at out patient clinics of our department. All patients were asked to fill a questionnaire to evaluate the interferon related side effects at every visit. Tumor necrosis factor alpha -238 and -308 polymorphisms were investigated with PCR-Restriction fragment length polymorphisms.
 Result(s) and Conclusion Arthralgia was present in 93.8% of patients. Exhaustion, loss of appetite, mount dryness and fever are the leading complaints of the patients. Median complaint scores were 9, 9.5, 11 and 5 at 4th, 12th, 24th and 48th week visits, respectively. Thrombocytopenia and leucopenia were detected in 8 (16%) and 5 (10%) patients, respectively. One-third of the patients reported depressive mood however, depression was diagnosed in 5 (10%) patients. TNF alpha promoter 238GG and 308GG allele was present in 42/50 and 43/50 patients, respectively. No association was found between TNF promoter allele and certain patient-reported side effect, complaint score, hematological and psychological adverse effects. TNF alpha promoter polymorphisms do not contribute to occurrence of IFN alpha treatment related side effects.

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.

Association of leishmaniasis with TNF alpha promoter and SLC11A1 gene polymorphisms in patients of two endemic areas in Mexico

Some Single Nucleotide Polymorphisms (SNPs) of interleukins and other modulatory molecules of the immune response play an important role in susceptibility to infectious diseases, particularly those involving intracellular parasites. In this study, we evaluated allele, genotype and haplotype associations of two SNPs of the TNF-α promoter and seven of the SLC11A1 gene in 79 patients with localized cutaneous leishmaniasis (CL) and 15 with visceral leishmaniasis (VL), compared with 127 and 89 locality paired controls, respectively, from two endemic areas of Chiapas State, Mexico. None of the TNF-α alleles and genotypes was associated either to CL or to VL. Alleles rs2276631-C (P = 0.02; OR [95%CI] = 2.11 [1.16–3.86]) and rs2279015-G (P = 0.005; OR [95%CI] = 2.42 [1.33–4.41]) of SLC11A1, were associated with susceptibility to VL, whereas genotypes rs2276631 C/C (P = 0.003; OR [95%CI] = 2.65 [1.41–5.00]) and rs2279015 G/G (P = 0.018; OR [95%CI] = 2.05 [1.15–3.64]) were significantly increased in CL and VL patients, respectively. Complete haplotypes involved in susceptibility were CGCCGDins with VL and CGCCADins with CL. CGCCA was the minimal susceptibility haplotype for CL and CCG for VL. Our data suggest that SLC11A1 gene polymorphisms might have a relevant role in the pathology of leishmaniasis, directing towards susceptibility outcome of this disease in residents of an endemic area.

TNF alpha Promoter Polymorphism May Confer Susceptibility to Rheumatoid Arthritis and Influence TNF alpha Production but not the Clinical Phenotype and Treatment Response

Rheumatoid arthritis (RA) is characterized by progressive joint damage predominantly mediated by proinflammatory molecules including the tumor necrosis factor alpha (TNF-α). Several studies have addressed the relationship between diversity of TNF-α gene and susceptibility to RA and its clinical phenotypes but the results have been inconsistent. We conducted a case-control study to analyze the potential influence of three functionally relevant TNF-α promoter variants on RA incidence and disease phenotypes and serum TNF-α levels in a genetically homogeneous south Indian Tamil population. Genomic DNA from 269 RA patients and 233 healthy controls (HC) were analyzed by TaqMan 5’-nuclease assay for the distribution of the following SNPs: TNF-α -857 C>T (rs1799724), TNF-α -308 G>A (rs1800629) and TNF-α -238 G>A (rs 361525). We found that the frequency of the TNF-α -238 GG genotype and G allele was higher in patients as compared to controls [Pc: 0.004, OR: 2.01, CI 95%: 1.23-3.29 and Pc: 0.004, OR: 1.89, CI 95%: 1.22-2.97 respectively]. The genotype and allele frequency of TNF-α -857 C>T and -308 G>A polymorphisms did not differ between patients and controls. Haplotype analysis revealed that the frequency of ancestral TNF-α (-857,-308,-238) C-G-G haplotype was more in patients than in HC (80% vs 74%, P: 0.03, OR: 1.39, CI 95%: 1.02-1.89). The CGA haplotype was found at a higher frequency in HC than in patients (10.6% vs 7%, P: 0.03, OR: 0.61, CI 95%: 0.38-0.96). We also found that TNF-α-857T allele was associated with significantly high titers of circulating TNF-α. Our data suggest that TNF-α -238 G allele, -238 GG genotype and the TNF-α –C-G-G ancestral haplotype may be associated with susceptibility to RA. In addition, the TNF-α-857 C>T variant might influence the TNF-α production.

The association between tumor necrosis factor alpha promoter polymorphisms and ankylosing spondylitis: A meta-analysis

Studies investigating the association between tumor necrosis factor (TNF)-alpha promoter polymorphisms and ankylosing spondylitis have reported conflicting results. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of this relationship. We performed a systematic search of the National Library of Medline and Embase databases before January 2013. This meta-analysis included 14 case-control studies, which included 1607 ankylosing spondylitis cases and 1910 controls. The combined results based on all studies showed that ankylosing spondylitis cases had a significantly lower frequency of -308GA [OR (codominant model)=0.81, 95% CI=0.66, 0.99, P=0.04], -857CT [OR (codominant model)=0.55, 95% CI=0.32, 0.94, P=0.03], -863AA [OR (codominant model)=0.11, 95% CI=0.01, 0.94, P=0.04], -863CA [OR (codominant model)=0.32, 95% CI=0.18, 0.58, P<0.001], and -1031TC [OR (codominant model)=0.44, 95% CI=0.25, 0.77, P=0.004] genotype. However, ankylosing spondylitis cases had a significantly higher frequency of -238AA [OR (recessive model)=7.43, 95% CI=3.66, 15.05, P<0.001] and -850TT [OR (recessive model)=2.49, 95% CI=1.16, 5.34, P=0.02; OR (codominant model)=2.83, 95% CI=1.28, 6.25, P=0.01] genotype. In the subgroup analysis by race, we found that ankylosing spondylitis cases had a significantly higher frequency of -238AA [OR (recessive model)=7.43, 95% CI=3.66, 15.05, P<0.001] genotype in Caucasians and lower frequency of -857CT [OR (codominant model)=0.53, 95% CI=0.30, 0.94, P=0.03] in Asians. Our meta-analysis suggests that TNF-alpha promoter polymorphisms at positions -238, -308, -850, -857, -863 and -1031 could have a small influence on ankylosing spondylitis susceptibility. But there is a lack of association of the TNF-alpha-376G/A and -646G/A polymorphisms with ankylosing spondylitis.

Tumour Necrosis Factor-Alpha Gene Expression in Chronic Hepatitis C Virus Infection.

Objective: Tumour necrosis factor (TNF)-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and – 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection. Aim of the work: The present study was to investigate the influence that the – 308and – 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection. Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between (20-56) years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of serum levels of TNF-α. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of TNF-α. Results: There was no statistically significant difference between chronic HCV patients and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF- alpha gene polymorphism in the – 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection. Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection. Recommendations: Our major concern was to improve the response to treatment in patients with chronic HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients.

Tumour Necrosis Factor-Alpha Gene Expression in Chronic Hepatitis C Virus Infection.

Objective: Tumour necrosis factor (TNF)-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and – 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection. Aim of the work: The present study was to investigate the influence that the – 308and – 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection. Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between (20-56) years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of serum levels of TNF-α. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of TNF-α. Results: There was no statistically significant difference between chronic HCV patients and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF- alpha gene polymorphism in the – 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection. Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection. Recommendations: Our major concern was to improve the response to treatment in patients with chronic HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients.

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.&#x0D; &#x0D; 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.&#x0D; &#x0D; 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.&#x0D; &#x0D; 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. &#x0D; &#x0D; S Afr J HIV Med 2012;13(2):72-77.

Meta‐analysis: polymorphisms in TNF‐α gene promoter and Crohn’s disease

Tumour necrosis factor alpha (TNF-alpha) is involved in the pathogenesis of Crohn's disease (CD). However, results on the association between the polymorphisms in TNF-alpha promoter and the risk of CD are inconsistent. To perform a quantitative synthesis for the genetic polymorphisms in TNF-alpha promoter and CD risk. Databases were searched (up to 2009) and 31 studies were included. Risks of CD associated with the polymorphisms in TNF-alpha promoter were assessed. Overall, individuals with -1031 TC+CC genotype had a slightly increased risk to develop CD compared with individuals with -1031 TT genotype (OR, 1.32; 95% CI, 1.03-1.70). In the further stratified analysis, we found Asians with the -1031T>C, -863 C>A and -857 C>T variant polymorphisms have almost one and a half CD risk compared with other genotypes (OR, 1.58; 95% CI, 1.16-2.15; OR, 1.55; 95% CI, 1.18-2.02; OR, 1.54; 95% CI, 1.19-1.99 respectively). We did not find -308 G>A variant associated with CD location and disease behaviours in stratified analysis. TNF-alpha polymorphisms in the promoter region might be used as a biomarker for CD risk prediction. Larger studies with mixed ethnicity subjects and stratified by clinical and sub clinical characteristics are needed to validate our findings.

The association between TNF-α promoter polymorphisms and ankylosing spondylitis: a meta-analysis

The relationship of TNF-alpha promoter polymorphisms and ankylosing spondylitis (AS) has been reported with conflicting results. We perform this meta-analysis to collect all the relevant studies up to date to further clarify the association of TNF-alpha promoter polymorphisms with AS. A review was conducted of studies reporting on the association between TNF-alpha promoter polymorphisms and AS susceptibility in Medline, Pubmed, Embase, and Web of Science. The numbers of individuals with various genotypes and alleles in both the case and control groups were extracted from relevant studies. Odds ratios (ORs) with 95% confidence interval (CI) were used to estimate the association. Fourteen eligible studies, contributing data on 3,880 subjects (1,766 patients; 2,114 controls), were included in this meta-analysis. The ORs of various comparisons indicated that there was no association between TNF-alpha 238, 308 polymorphisms, and AS susceptibility in the overall population. For HLA-B27+ population, although the frequency of 308 A allele decreased in AS patients (OR = 0.721; 95%CI = 0.522-0.995), the result was no longer statistically significant after excluding the Hardy-Weinberg equilibrium violation studies (OR = 1.150; 95%CI = 0.568-2.310). No relationship was found between TNF-alpha promoter 238 polymorphisms and AS in HLA-b27+ population. No association was found between TNF-alpha promoter 238/308 polymorphisms and ankylosing spondylitis susceptibility in both the overall and HLA-B27+ population.

Association Between Polymorphism of Tumor Necrosis Factor-α Promoter and Response to Lamivudine Treatment in Patients with Chronic Hepatitis B

TNF-alpha promoter polymorphism is known to play an important role in the immunopathogenesis of infection of hepatitis B virus. We investigated whether polymorphisms of TNF-alpha promoter at position -308 or -238 had associations with the response to lamivudine treatment. A total of 89 healthy subjects (control group) and 225 patients with chronic hepatitis B treated with lamivudine were included in this study. Polymorphisms of TNF-alpha promoter at position -308 and -238 were analyzed by polymerase chain reaction. Recruited patients were classified according to the outcome of lamivudine treatment into the responder (103 patients) or non-responder (122 patients) group. The numbers of A allelic polymorphism of TNF-alpha promoter at position -238 were four (2.2%) in the control, five (2.4%) in the responder and 19 (7.8%) in the non-responder group. The A allele was noted significantly more frequently in the responder than non-responder group (P = 0.012). At position -308, a significant difference was observed between the control group (14; 7.9%) and total chronic hepatitis B patients (15; 3.3%) (P = 0.015). Our study demonstrated that the non-response to lamivudine treatment in patients with chronic hepatitis B might be related to the A allelic polymorphism of TNF-alpha promoter at position -238.

TNF‐α Polymorphisms in Primary Biliary Cirrhosis: A Northern and Southern Italian Experience

Specific HLA alleles and immunoregulatory genes have been evaluated in primary biliary cirrhosis (PBC), but data are discordant. We determined whether TNF-alpha promoter polymorphisms (G-308A and G-238A) and alleles of HLA class II (HLA-DRB1) might be associated either with PBC occurrence and severity in Italian populations from two distinct areas. The distribution of TNF1 (G/G) genotype did not differ either between patients and controls or between patients from Northern and Southern Italy. Contrariwise, the HLA-DRB1*08 appeared positively linked to the occurrence of disease (8.4% in patients vs. 2.5% in controls, P = 0.003), whereas the HLA-DRB1*13 appeared to be protective, being more frequent in controls (12.8%) than in patients (7%) (P = 0.038). Neither positively nor negatively associated alleles of the two genomic loci had an effect on disease progression. We report a distinct genetic risk of developing PBC in the Italian population, with no interaction between the HLA and TNF alleles.

Lack of association of TNF- promoter polymorphisms with ankylosing spondylitis: a meta-analysis

Genetic factors, in addition to the HLA-B27, could play a role in the pathogenesis of AS. TNF-alpha promoter polymorphisms have been reported to be associated with AS susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether TNF-alpha promoter polymorphisms confer susceptibility to AS. We conducted a random effect meta-analysis on the association of the A/A genotype (the recessive effect), the A/A + A/G genotype (the dominant effect) and the A allele of the TNF-alpha -308 and -238 polymorphisms with AS. Eight studies, consisting of seven European studies and one Latin American study, were included in this meta-analysis. Any association between AS and the TNF-alpha -308 A allele was not found [odds ratio (OR) = 0.911; 95% CI 0.512, 1.286; P = 0.636; I(2) = 73.8]. There was also no association of the TNF-alpha -308 AA and AA+AG genotypes with AS. Meta-analysis of the TNF-alpha -238 polymorphisms showed no association with AS (OR for A allele = 0.930; 95% CI 0.498, 1.737; P = 0.821; I(2) = 71.6). Subgroup analysis by ethnicity and HLA-B27 positivity did not change the results for the association of the TNF-alpha -308 and -238 polymorphisms with AS. This meta-analysis including 2247 subjects has shown that there is a lack of association of the TNF-alpha -308 A/G and -238 A/G polymorphisms with AS.

Autoimmune Pancreatitis Associated With High Prevalence of Gastric Ulcer Independent of Helicobacter pylori Infection Status

The relationship between Helicobacter pylori status and host tumor necrosis factor alpha (TNF-alpha) promoter susceptibility in ulcers inautoimmune pancreatitis (AIP) is unknown. We sought to study the frequency of peptic ulcer, the association of peptic ulcer with H. pylori and host TNF-alpha promoter haplotype in AIP and nonautoimmune chronic pancreatitis. Esophagogastroduodenoscopy (EGD) was performed in 40 patients with AIP and 113 patients with nonautoimmune chronic pancreatitis (CP). The status of H. pylori infection was determined. Genotyping and 5-locus haplotype assembly of the TNF-alpha promoter were performed. The correlation between clinical characteristics, endoscopic findings, Helicobacter pylori infection status, and TNF-alpha promoter polymorphism and haplotype was analyzed. The frequencies of gastric ulcer (GU) was higher in patients with AIP compared with patients with nonautoimmune CP (22.5% vs 4.4%, P = 0.001). Duodenal ulcer (DU) was more prevalent than GU in both patients with AIP and patients with nonautoimmune CP. There was no difference in the positive status of H. pylori and TNF-alpha promoter polymorphism/haplotype. Our results demonstrated that GU was more prevalent in AIP compared with nonautoimmune CP. Positive H. pylori status and host TNF-alpha promoter susceptibility could not explain the pathogenesis of higher GU prevalence and pathogenesis of AIP in our population.

Higher LPS-stimulated TNF-α mRNA levels in peripheral blood mononuclear cells from Chinese ankylosing spondylitis patients with −308G/A polymorphism in promoter region of tumor necrosis factor: association with distinct A33/B58/Cw10 haplotypes

To investigate the effects of TNF-alpha -308, -238 promoter polymorphisms on TNF-alpha transcription in B27 positive Chinese patients with ankylosing spondylitis (AS). The possible relationship between polymorphisms, MHC antigens, and quantitative TNF-alpha mRNA expression were evaluated. Single nucleotide polymorphisms (SNPS) of TNF-alpha -308 and -238 were performed by PCR-amplification refractory mutation system method (PCR-ARMS) in sixty-seven B27-positive AS patients and 60 HLA-B27 positive healthy controls in Chinese. Quantitative measurement of TNF-alpha mRNA in peripheral blood mononuclear cells was performed with real time RT-PCR. The polymorphisms were correlated to quantitative TNF-alpha mRNA, and MHC antigens (determined by SSP method) in AS patients. The prevalence rate of both -308G/A and -238G/A TNF-alpha promoter polymorphisms in patients were not significantly different from those in normal subjects. However, a significant high LPS-stimulated TNF-alpha mRNA expression was found in peripheral blood mononuclear cells from patients with promoter -308G/A polymorphism (TNF2) as compared to those in -308G/G genotype (TNF1). Furthermore, -308G/A polymorphism in patients was found to be tightly associated with distinct haplotypes of A33/B58/Cw10 [12 out of 14 -308G/A patients (85.7%) versus none in 53 -308G/G patients], independent of B27 antigen. HLA-A33-B58-Cw10 haplotypes associated TNF-alpha promoter -308G/A polymorphism might play an important role in disease pathogenesis of AS in Chinese population, partially related to a driving force of a higher TNF-alpha production. It confirms once again the importance and complexity of MHC related molecules in disease pathogenesis of AS.

Combined effect of tumour necrosis factor‐α and interleukin‐13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma

TNF-alpha and IL-13, two pivotal pro-inflammatory cytokines, are increased in asthmatic airways and may be linked to asthma susceptibility and/or bronchial hyperresponsiveness (BHR). We investigated the association between the TNF-alpha-308G/A polymorphism and asthma susceptibility or asthma-related phenotypes in Korean children with asthma, and tested for a combined effect with IL-13 polymorphisms. Asthmatic children (n=719) and non-atopic healthy control children (n=243) were evaluated for asthma phenotypes including total serum IgE and BHR to methacholine. Genotypes were determined by PCR-restriction fragment length polymorphism analysis. The allele frequency of TNF-alpha-308A in asthmatics (14.1%) was higher than that in control children [8.7%, odds ratio (OR) 1.72, 95% confidence interval (CI) 1.05-2.82]. Significantly lower PC(20) values were found in asthmatic children carrying one or two copies of the TNF-alpha risk allele (-308A) vs. those homozygous for the common allele (P=0.026). Combined analysis revealed that atopic asthmatic children co-inherited the risk alleles of TNF-alpha-308G/A and IL-13 +2044G/A more frequently than control children (aOR 1.91, 95% CI 1.00-3.65), and asthmatic children co-inheriting both risk alleles had significantly lower PC(20) values vs. asthmatic children homozygous for the common alleles (P=0.024). The TNF-alpha promoter polymorphism (-308G/A) may be associated with asthma susceptibility and BHR in Korean children with asthma. In addition, there appears to be a synergistic effect between the TNF-alpha promoter polymorphism and an IL-13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.

Tumor Necrosis Factor-Alpha Polymorphisms in Ulcerative Colitis-Associated Colorectal Cancer

Ulcerative colitis (UC) is characterized by chronic recurrent mucosal inflammation. Genetic studies in UC have indicated linkage to chromosome 6 in the region of the tumor necrosis factor-alpha (TNF-alpha) gene, a potent proinflammatory cytokine. TNF-alpha production is influenced by multiple factors including the type of immune cell and its level of activation. However, several single nucleotide polymorphisms (SNP) in the promoter region of TNF-alpha have been correlated with either increased or decreased production, indicating that regulation of TNF-alpha is in part genetic. Because UC patients are at increased risk for developing colorectal cancer (CRC), we investigated if there was an association between SNPs in the promoter of the TNF-alpha gene and UC-CRC. DNA was extracted from formalin-fixed, paraffin-embedded tissue from 114 UC-CRC cases and 114 UC-no CRC controls. Controls were frequency matched on duration and extent of colitis, age, ethnicity, and gender. All 228 tissue samples were analyzed for five TNF-alpha promoter polymorphisms (-238[G-->A], -308[G-->A], -857[C-->T], -863[C-->A], and -1031[T-->C]) using PCR and sequencing. The -308(G-->A) SNP was significantly associated with UC-CRC cases at both the allele and genotype level (P < 0.0001). No other SNPs were significantly associated with UC-CRC. We report a novel finding of a strong association between the -308(G-->A) SNP and UC-CRC. Complete elucidation of the mechanism of UC-CRC carcinogenesis will require investigation of other genes involved in modulating inflammation, but our results suggest that some UC patients may have additional genetic predispositions toward developing UC-CRC.

Tumor necrosis factor - α and transforming growth factor - β1&lt;i&gt; &lt;/i&gt;polymorphisms in bronchial asthma

Bronchial asthma is a complex genetic disorder regulated by the release of cytokines and inflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta1) cytokines play pivotal roles in the inflammatory response of the airways. Differential production of these two cytokines is associated with allelic variations in the transcriptional regulatory region of these genes. The objective of the present study was to investigate G-308A TNF-alpha and C-509T TGF- beta1 polymorphisms for their association with Bronchial Asthma. DNA isolated from 123 asthmatics and 100 normal healthy controls were screened for these polymorphisms using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) methods, developed in our laboratory. Significant allelic association was observed between G-308A TNF-alpha polymorphism and asthma (P = 0.031) while no association was observed with C-509T TGF- beta1 polymorphism (P = 0.207). Further sub-grouping based on either allergic response or family history failed to reveal any statistical significance among the groups or with controls. The interaction between these polymorphisms revealed statistically significant association between the high producer genotype alleles of TNF-alpha and TGF-beta (A/T) and asthma (P = 0.016). The present study reports, for the first time, the role of two polymorphisms, in concert, for their association with asthma in an Indian population. Our study supports the findings that the G-308A TNF-alpha promoter polymorphism is a risk factor for asthma and furthermore suggests that the patients with high producer alleles for TNF-alpha (-308) and TGF-beta (-509) have the highest risk of getting this disease in the Punjabi population.

Association of HLA‐DRB1*13 and TNF‐α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population

Considerable evidence suggests that host genetic factor play an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection in several ethic groups. Association study was performed included 150 chronic HBV patients, 100 resolved hepatitis B and 150 healthy individuals with similar ethic background. Interestingly, human leucocyte antigen (HLA)-DR13 show a strong association with the clearance of HBV [odds ratio (OR) = 0.04, 95% confidence interval (CI) = 0.00-0.26, corrected P-value (P(c)) = 0.0008] similar to reports from several ethic groups. TNF-alpha promoter polymorphisms (-863, -308 and -238) were also analysed. Only -863 C allele was found to be significantly decreased in chronic HBV patients compared with healthy control (P(c) = 0.03, OR = 0.54, 95% CI = 0.35-0.84 respectively). This -863C allele was not in linkage disequilibrium with HLA-DR13 suggesting that other genetic markers linked with -863C might influence clearance of chronic HBV infection in Thai. When stratified chronic HBV patients into patients without hepatocellular carcinoma (HCC) and with HCC, the -863 A allele was significantly increased in the HCC group compared to healthy control (P(c) = 0.003, OR = 2.61, 95% CI = 1.49-4.60). Haplotype analysis (-863/-308/-238) revealed that the homozygosity of the haplotype (CGG/CGG) was a protective marker for HCC (OR = 0.37, 95% CI = 0.17-0.79, P(c) = 0.02). One can propose that carriers of -863A genotype are associated with increased levels of TNF-alpha in the liver in response to HBV infection and induce hapatocyte damage that may finally lead to HCC development. Additional study is needed to validate these finding and to further explore the genetic pathogenesis of HBV infection.

Combination of Helicobacter pylori Strain and Tumor Necrosis Factor‐α Polymorphism of the Host Increases the Risk of Peptic Ulcer Disease in Children

Helicobacter pylori infection is probably acquired in childhood and causes a vigorous immune response. It is unclear why only a subgroup of infected children develops peptic ulcer disease. We have previously reported that iceA1 strains tend to be associated with duodenal disease in children. However, the pathogenesis probably does not depend solely on the H pylori strain but also on the variability of the host response. The aim of this study was to assess the significance of tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism in relation to infection with H pylori strains in children. A total of 113 antral biopsies of H pylori-positive children (ages 2-18 years) were analyzed. Of these, 23 had duodenal disease, including erosive duodenitis and/or duodenal ulceration, and 90 had gastritis only. H pylori infection was diagnosed by bacterial culture and histology. Patient genomic DNA extracted from the antral biopsy was used to characterize the genetic polymorphism of TNF-alpha promoter at nucleotide positions -308 and -238 by polymerase chain reaction-based restriction fragment-length polymorphism. All H pylori strains were examined for cytotoxin-associated gene A and induced-by-contact-with-epithelium gene (iceA1). A total of 31% of children with duodenal disease were infected with iceA1 positive strains and had the -238 G to A polymorphism in the TNF-alpha gene vs only 1.6% of children with gastritis alone (P < 0.0005). The combination of bacterial iceA1 and TNF-alpha 238 G to A polymorphism may be a risk factor for peptic ulcer disease in children infected with H pylori. Larger studies are needed to confirm this association.