Tumor Necrosis Factor Polymorphisms Research Articles

Tumour necrosis factor (-308A) polymorphism in pre-eclampsia: Meta-analysis of 16 case–control studies

Tumour necrosis factor (-308A) polymorphism in pre-eclampsia: Meta-analysis of 16 case–control studies

Tumour necrosis factor (−308A) polymorphism in very preterm infants with bronchopulmonary dysplasia: a meta-analysis

Background:Excessive release of tumour necrosis factor (TNF) may contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) in very preterm infants. It has been proposed that the risk of developing BPD...

Tumour necrosis factor (‐308A) polymorphism in pre‐eclampsia: Meta‐analysis of 16 case–control studies

The guanine to adenine transition at position -308 nucleotides in the tumour necrosis factor promoter region (TNF -308A) is a putative genetic risk factor for pre-eclampsia/eclampsia (PE/E). However, association studies have reported conflicting findings and have generally been underpowered to exclude modest effect sizes. To assess and synthesise the available evidence for the association of the TNF (-308A) polymorphism with PE/E. Systematic review and random effects meta-analysis of genetic association studies. Sixteen eligible case-control studies in which a total of 1919 patients with PE/E and 2374 controls participated were identified. The studies were generally small but of reasonable methodological quality. Random effects meta-analysis improved the precision of the estimate of effect size but did not detect a statistically significant association: pooled relative risk 1.02 (95% confidence interval 0.86 to 1.20). The available data are not consistent with more than a very modest association between the TNF (-308A) allele and PE/E. Screening pregnant women for this allele in order to guide antenatal surveillance or treatment is unwarranted. Future research efforts should focus on alternative candidate genes.

Independent Association of Tumor Necrosis Factor Polymorphism with Type 1 Diabetes Susceptibility

The contribution of SNPs in TNF genes to type 1 diabetes (T1D) is not well established and may be confounded by the linkage disequilibrium within the HLA genes. Seven SNPs in the TNF genes (TNFA and TNFB) were genotyped in a Korean cohort (398 T1D patients and 1422 nondiabetic controls), along with HLA DRB1, DQB1, and MICA (MHC class I chain-related genes). Among them, three SNPs (TNFB+318, TNFA-857, and TNFA-308) and two common TNF haplotypes showed significant association with the risk of T1D (P= 5 x 10(-3)-10(-5)). T1D patients were more often heterozygous for the alleles at the TNFB+318 (OR = 1.7, P= 10(-3)) and TNFA-308 (OR = 1.7, P < 10(-5)) than were the controls. Genetic association analyses of the DRB1, DQB1, and MICA alleles with the risk of T1D revealed dramatic associations in several alleles as expected. Independent analyses to discern the genetic effects of TNF polymorphisms on the risk of T1D suggested that these genetic influences might be not totally dependent on the nearby HLA genes. Our results support the hypothesis that two susceptibility loci in the MHC (one in the HLA class II and another in the central MHC region) act epistatically to increase susceptibility to T1D.

Combining effects of polymorphism of tumor necrosis factor α 5′-flanking region and HLA-DRB1 on radiological progression in patients with rheumatoid arthritis

We examined whether polymorphisms upstream of the TNF-alpha gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen's score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5'-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen's score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

Association of TNF promoter polymorphisms with type 1 diabetes in the South Croatian population.

Type 1 diabetes mellitus (TIDM) is an autoimmune disease characterized by the destruction of pancreatic p cells. Tumor necrosis factor (TNF) is a pleotropic cytokine with potent immunomodulatory and inflammatory activity. Association studies of TNF polymorphisms and type 1 diabetes (TIDM) frequently demonstrated TNF involvement with TIDM. Although TNF may play an important role in the pathogenesis of TIDM, the genetic association of TNF región with the disease has not been conclusive because of the strong linkage disequilibrium with HLA genes. In this study, we examined two TNF promoter variants (rs 1800629 at position -308, and rs361525 at position -238) for TIDM association in 233 patients and 144 controls from the population of South Croatia. A higher frequency of TNF -308 A alíele and also, a more frequent specific -308A -238G haplotype in TIDM patients were observed with a limited significance. However, we did not find strong evidence of association of TNF promoter polymorphisms with TIDM. In order to elucidate the trae contribution of TNF to TIDM susceptibility in our population, more comprehensive studies with HLA adjustment in a larger sample are required.

Polymorphisms of the TNF, CD14, and HSPA1B Genes in Patients With Acute Alcohol-Induced Pancreatitis

Genotype assessment has been suggested to be a tool for predicting disease severity in acute pancreatitis (AP). To study this hypothesis, we performed genotype analysis of tumor necrosis factor (TNF) -308 A/G, CD14 -159C/T, and HSPA1B +1267 A/G polymorphisms. This is a case-control association study of 397 patients with AP (214 of whom had an alcohol-induced AP) and 300 controls. The control group comprised 218 subjects with detailed data of alcohol consumption, 70 of whom were heavy drinkers (daily alcohol intake >40 g), and 92 blood donors. The severity of AP was determined according to the Atlanta classification. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-assisted genotyping method. Major allele frequency in TNF gene was 0.87 for patients with AP and 0.86 for controls. For CD14, the gene major allele frequency was 0.60 for patients and 0.63 for controls. For HSPA1B, the major allele frequencies were 0.52 for patients and 0.49 for controls, respectively. The allele frequencies did not differ significantly between AP patients with organ failure and those with mild disease, patients with alcohol-induced AP, or those with biliary AP. The patients with septic infectious complications (n = 47) had genotype distribution no different from those with mild, uncomplicated disease (n = 245). The TNF, CD14, and HSPA1B polymorphisms studied seem not to play a role in determining the severity of AP or the risk of alcohol-induced AP and thus do not serve as a tool for predicting disease severity.

Association between susceptibility of endometriosis and the gene polymorphism of tumor necrosis factor

To evaluate the association between the susceptibility of endometriosis (EMS) and the gene polymorphism of tumor necrosis factor (TNF) in Chinese Han population. Peripheral blood samples were collected from 76 EMS patients and 87 normal controls. PCR-RFLP was used to detect the single base change polymorphism in both TNFalpha gene and TNFbeta gene. The allele frequencies of the TNFalpha polymorphism were 0.9474 and 0.9253 in the EMS patients and the control group respectively, and the TNFbeta polymorphism were 0.0526 and 0.0747 respectively. The allele frequencies of the TNFbeta1 polymorphism were 0.4605 and 0.5115 in the EMS patients and the control group, and the TNFbeta2 polymorphism were 0.5395 and 0.4885. No difference in the gene and genotype frequencies of TNFalpha and TNFbeta was noted in the EMS patients and normal controls (all P > 0.05). TNF gene polymorphism has no effect on EMS in Chinese Han population. Ethnic difference may exist in TNF allele frequency.

Family-based association of a low producing lymphotoxin-α allele with reduced Plasmodium falciparum parasitemia

Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymorphisms have been associated with severe malaria, mild malaria, and parasitemia. Lymphotoxin-alpha gene ( LTA) that belongs to the TNF family is one such candidate gene. Here we report the family-based association analysis of a cis-regulatory lymphotoxin-α polymorphism with parasitemia in two independent populations living in Burkina Faso. Analysis of 199 subjects (34 families) living in an urban endemic area revealed the association of the low producing LTA + 80A allele with reduced parasitemia. Furthermore, there was evidence of significant LTA + 80-by-age and LTA + 80-by-gender interactions. In another set of 318 residents (55 families) in a rural endemic area, we found both the association of the low producing LTA + 80A allele with reduced parasitemia and LTA + 80-by-age and LTA + 80-by-gender interactions. This study suggests that LTA + 80 polymorphism influences parasitemia and acts in an age- and gender-dependent manner.

Tumour necrosis factor gene polymorphisms are associated with COPD.

Tumour necrosis factor (TNF)-alpha has been shown to be an important factor in animal models of chronic obstructive pulmonary disease (COPD). However, human studies of TNF polymorphisms in COPD have been equivocal. Six TNF single nucleotide polymorphisms (-1031C/T, -863C/A, -857C/T, -237G/A, -308G/A and +487G/A) and their haplotypes were investigated in 423 Caucasian smokers (298 patients with spirometric evidence of COPD and 125 without airflow obstruction). The -308 minor allele (A) had a higher odds ratio (OR) of being associated with COPD in multivariate analysis (controlling for age, sex, pack-yrs; OR 1.9, 95% confidence interval (CI) 1.1-3.2) and was also associated with worse forced expiratory volume in one second/forced vital capacity. The -237 minor allele (A) had a lower OR of being associated with COPD (OR 0.40, 95% CI 0.19-0.86). In COPD patients, the -857 minor allele (T) had a lower OR of being associated with severe stages of COPD (Global Initiative for Obstructive Lung Disease stage III and IV versus stage I and II, OR 0.46, 95% CI 0.24-0.88). Other TNF single nucleotide polymorphisms were not associated with COPD but the -1031/-863 haplotype CC/TC had a lower OR in COPD patients versus smoking controls (OR 0.22, 95% CI 0.05-0.97). The present study adds further evidence that tumour necrosis factor genotypes play a role in susceptibility to cigarette smoke.

Advance in the relationship between inflammatory bowel disease and tumor necrosis factor polymorphisms

Advance in the relationship between inflammatory bowel disease and tumor necrosis factor polymorphisms

Association of TNF promoter polymorphisms with type 1 diabetes in the South Croatian population

Type 1 diabetes mellitus (TIDM) is an autoimmune disease characterized by the destruction of pancreatic p cells. Tumor necrosis factor (TNF) is a pleotropic cytokine with potent immunomodulatory and inflammatory activity. Association studies of TNF polymorphisms and type 1 diabetes (TIDM) frequently demonstrated TNF involvement with TIDM. Although TNF may play an important role in the pathogenesis of TIDM, the genetic association of TNF región with the disease has not been conclusive because of the strong linkage disequilibrium with HLA genes. In this study, we examined two TNF promoter variants (rs 1800629 at position -308, and rs361525 at position -238) for TIDM association in 233 patients and 144 controls from the population of South Croatia. A higher frequency of TNF -308 A alíele and also, a more frequent specific -308A -238G haplotype in TIDM patients were observed with a limited significance. However, we did not find strong evidence of association of TNF promoter polymorphisms with TIDM. In order to elucidate the trae contribution of TNF to TIDM susceptibility in our population, more comprehensive studies with HLA adjustment in a larger sample are required.

Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)-α levels in Asian Indians

Tumour necrosis factor (TNF)-alpha, an important proinflammatory cytokine, has been implicated in the pathogenesis of sarcoidosis, a multi-systemic granulomatous disorder of unknown aetiology. Here, we report for the first time the association of TNF haplotypes and genotypes with sarcoidosis and its prognosis in the Indian population. Five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene were genotyped in a clinically well-defined cohort of North-Indian patients with sarcoidosis (n = 96) and their regional controls (n = 155). Serum TNF-alpha (sTNF-alpha) and serum angiotensin converting enzyme (SACE) levels were measured and correlated with genotypes and haplotypes. The TNFA_-1031 and TNFA_-863 polymorphisms were identified as markers for disease onset (FET P = 0.006 and 0.042 for TNFA_-1031 and TNFA_-863, respectively). Additionally, the allele A of LTA_NcoI polymorphism was shown to be prevalent in the 'no treatment' group (FET P = 0.005), while the G allele was associated with frequent relapses on drug withdrawal (P = 0.057). Furthermore, the TNFA-308G>A and the TNFA-238G>A polymorphisms were found to influence sTNF-alpha (P = 0.054 and 0.0005, respectively) and SACE levels (P = 0.0017 and 0.056, respectively). The haplotype frequencies were significantly different in the patients and the controls (P = 0.0067). The haplotype GTCCGG was identified as the major risk/susceptibility haplotype (P = 0.003) and was associated with increased SACE levels in the patient population. In conclusion, our study suggests an association of TNF polymorphisms with sarcoidosis.

Gene polymorphisms of tumor necrosis factor ??-308 and interleukin 10-1082 among asthmatic Egyptian children

Gene polymorphisms of tumor necrosis factor ??-308 and interleukin 10-1082 among asthmatic Egyptian children

Possible Association of CTLA-4 Gene Polymorphism With Cyclosporine-Induced Gingival Overgrowth in Kidney Transplant Recipients

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T −318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT) n in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-α on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO−), and 26 tacrolimus (Tac)-treated without GO (TacGO−). The SNPs of CTLA-4 (−318 C>T and +49 A>G), IL-2 (−330T>G), and TNF-α (−308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT) n genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 −318C>T, IL-2, and TNF-α. However, patients with CsAGO+ showed differences from CsAGO− for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO− ( P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO− were noticed for the genotype distribution of CTLA-4 (AT) n ( P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.

Polymorphisms in tumor necrosis factor and other cytokines as risks for infectious diseases and the septic syndrome

An increasing number of genetic association studies have implicated polymorphisms of cytokine genes as host genetic factors influencing susceptibility to infectious disease, primarily using a candidate gene approach based on knowledge of disease pathogenesis. The application and limitations of association studies are reviewed together with the impact of recent advances in single nucleotide polymorphism mapping on strategic approaches to defining genetic susceptibility loci. It often remains unclear whether associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype, and experimental approaches to investigating the functional impact of polymorphisms in noncoding regulatory DNA sequences are discussed. An overview of genetic associations of cytokine genes with infectious disease is presented, together with discussion of recent studies in a number of infectious diseases including hepatitis, HIV, malaria, and sepsis.

Role of Tumor Necrosis Factor Gene Polymorphism (-308 and -238) in Colorectal Cancer Susceptibility

Purpose: The purpose of this study is to investigate the potential association of tumor necrosis factor-α (TNF-α) promoter polymorphisms (-308 G>A and -238 G>A) with colorectal cancer susceptibility. Methods: The study included 77 patients with colorectal cancer and 100 healthy controls. The polymorphisms were genotyped for these TNF-α polymorphisms by PCR-Pyrosequencing (Fig. 1). The distributions of TNF-α promoter polymorphisms were compared between cancer patients and healthy controls by the chi-square test. Odds ratios (OR) and 95% confidence intervals (CI) were also calculated. Results: The Genotype distributions and allele frequencies of the -308 (rs361525) and -238 (rs1800629) TNF-α polymorphism in cancer patients and controls are shown in Table 1. Although the TNF-308A allele frequency was lower in the cancer group compared with the control group (7.8% vs. 14.5%) and TNF-238A allele frequency was higher (7.8% in cancer group vs. 6% in controls), the observed differences were not statistically significant (P > 0.05). The odds ratio for cancer in subjects with the TNF-308A allele was 0.55(95% CI, 0.24–1.25) and with the TNF-238A allele was 1.05 (95% CI, 0.37–3.0).Table 1: Distributions of the two tumor necrosis factor (TNF) polymorphisms in colorectal cancer patients and healthy controlsConclusion: We found no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF-α and susceptibility to colorectal cancer in an Iranian population.[figure1]

A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis

Objective:To determine whether tumour necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of the response to adalimumab (ADA) in rheumatoid arthritis (RA).Methods:This ancillary study to the...

Clinical and genetic risk factors for pneumonia in systemic lupus erythematosus

To define the contribution of polymorphisms in genes encoding tumor necrosis factor (TNF), mannose-binding lectin (MBL), and Fcgamma receptor IIa (FCGR2A) as well as clinical factors, to the development of pneumonia in patients with systemic lupus erythematosus (SLE). We studied 282 SLE patients from a multiethnic cohort. Pneumonia events and clinical risk factors for pneumonia were identified through medical record review. Genotyping was performed for MBL (+223, +230, and +239), TNF (-308, -238, and +488), and FCGR2A (-131H/R) polymorphisms. Univariate analyses were performed to identify clinical and genetic risk factors for pneumonia. Covariates for multivariate analysis included sex, ethnicity, treatment with immunomodulators, and leukopenia. Forty-two patients (15%) had at least 1 episode of pneumonia. Polymorphism of the TNF gene, particularly the -238A allele and a related haplotype, revealed the most striking and consistent association with pneumonia in univariate analyses. Results of multivariate analyses indicated an odds ratio (OR) for the TNF -238A allele of 3.5 (P = 0.007) and an OR for the related haplotype of 5.4 (P = 0.001). Male sex, treatment with immunomodulators, and leukopenia also influenced the risk of pneumonia. These findings suggest that specific TNF variants may identify SLE patients who are at particularly high risk of developing pneumonia. Given the prevalence and excessive morbidity associated with pneumonia in SLE, these findings have clinical relevance and provide insight into the pathogenesis.

TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline

Objectives: Endotoxin exposure induces airway inflammation, hyper-responsiveness and higher expression of tumour necrosis factor (TNF). This study was conducted to investigate whether TNF polymorphisms modify the effect of endotoxin exposure...