TNF2 Allele Research Articles

Genetic polymorphism at position-308 in the promoter region of the tumor necrosis factor (TNF): implications of its allelic distribution on susceptibility or resistance to diseases in the Chilean population.

Several single-nucleotide polymorphisms have been identified in the human TNF gene promoter. The polymorphism at position-308 (TNF-308), which involves substituting G for A and designing the TNF2 allele, leads to a higher rate of TNF gene transcription than the wild-type TNF1 allele in in vitro expression studies. It has also been linked to increased susceptibility to a variety of illnesses. Using PCR-RFLP analysis we detected significant differences in the TNF-308 genotypes of Chilean and other populations. We conclude that there is a gradient in the distribution of the TNF2 allele according to ethnicity; we have also hypothesized that populations bearing a higher proportion of the TNF2 allele may have an increased predisposition toward or incidence of several chronic metabolic, degenerative, inflammatory and autoimmune diseases.

Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia.

Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular tumor necrosis factor alpha (TNFalpha), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, TNFalpha gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A TNFalpha gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNFalpha plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNFalpha as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component.

Contribution of TNF-alpha and IL-10 gene polymorphisms to graft-versus-host disease following allo-hematopoietic stem cell transplantation.

Some cytokines are believed to play a role in the development of acute and chronic GVHD after allo-hematopoietic stem cell transplantation. It has been reported that TNF-alpha and IL-10 gene polymorphisms are associated with the production of those cytokines and the development of graft failure after organ transplantation and systemic lupus erythematosus. We examined whether TNF-alpha and IL-10 gene polymorphisms affect the severity of acute GVHD (aGVHD) and chronic GVHD (cGVHD). Sixty-two and 54 patients were available for the analysis of aGVHD and cGVHD, respectively. We analyzed the gene polymorphisms derived from pre- and post-transplant blood cells. Donor-derived TNF2 allele (A) was more frequently detected in patients with aGVHD III/IV than those aGVHD 0-II (2/6 vs 2/56) (P = 0.04). The donors of the patients with cGVHD more frequently possessed a greater number of alleles (allele 13 or more which contain 26 or more CA repeats) in IL-10.G than those without (13/26 vs 5/28) (P = 0.02), and the patients with cGVHD had more CA repeats in donor-derived IL-10.G than those without (mean = 25.2 vs 23.4) (P = 0.01). Donor-derived TNF-308 and IL-10.G alleles may contribute to severe aGVHD and cGVHD, respectively, and will help us distinguish those patients at high risk for GVHD.

Tumor necrosis factor gene polymorphism and septic shock in surgical infection.

To evaluate the relationship of the genotype distribution of the tumor necrosis factor (TNF)-alpha polymorphism with regard to the plasma TNF-alpha concentration and the development of septic shock as well as mortality of infected patients in a surgical intensive care unit (SICU). A total of 112 postoperative critically ill infected patients were prospectively enrolled. SICU of a tertiary university-affiliated medical center. Patients who were consecutively admitted to the SICU because of surgical infection with sepsis. Blood sampling. Blood sample was obtained 24 hrs after intensive care unit (ICU) admission or within 2 hrs after the onset of septic shock to determine the plasma TNF-alpha level and to analyze the genotype of the biallelic polymorphism of the TNF-alpha. The allele frequency of the TNF2 in our infected ICU patients was 12%. Forty-two (37.5%) patients admitted fulfilled the criteria of septic shock during their ICU stay. Patients carrying the TNF2 allele were not more likely to develop septic shock, nor did they have a higher mortality rate. In the patients with septic shock, those carrying the TNF2 allele had a significantly higher mortality rate than those with the homozygous TNF1 genotype (92% vs. 62%, p < .05). In those who developed septic shock, the TNF2 allele was significantly associated with higher TNF levels. In patients admitted to SICU with surgical infection, the frequency of TNF2 allele was higher than in the general population. SICU patients with TNF2 allele did not show a higher incidence of developing septic shock, nor was there a higher baseline TNF-alpha level after infection. However, once septic shock had developed, the mortality rate was higher in those patients carrying the TNF2 allele.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Pathogenesis of nerve damage in leprosy: genetic polymorphism regulates the production of TNF alpha.

Studies carried out over the last decade have strongly suggested that TNF alpha both overtly participates in the cell-mediated immune response against Mycobacterium leprae, and is overproduced during reaction. In addition, reactions are intimately related to the onset of nerve damage. Finally, TNF alpha has been implicated in the pathogenesis of many human and experimental autoimmune peripheral neuropathies that, as in leprosy, result in demyelination and axonal lesions. Because of recent findings associating human TNF alpha mutant alleles at the -308 position with increased production of TNF alpha in many immunological and infectious diseases, an investigation of the role of TNF2 in predisposing leprosy patients to reaction has been undertaken. Analysis of 300 patients with leprosy--210 multibacillary and 90 paucibacillary--has shown that the percentage of reactional patients was similar among both carriers and non-carriers of the TNF2 allele. However, a separate analysis of 57 carriers of TNF2 found that reactions occurred much more frequently among heterozygous than among homozygous patients. Moreover, the frequency of neuritis was somewhat greater among the heterozygous patients than among the non-carriers. Enhanced serum levels of TNF alpha have been noted in both TNF-1 and TNF-2 mutant patients in the course of leprosy reaction. Our observations to date suggest that other factors not related to the presence of the mutant gene may lead to the TNF alpha hyper-responsiveness observed during reaction.

Donor polymorphism of tumor necrosis factor gene: relationship with variable severity of hepatitis C recurrence after liver transplantation.

Hepatitis C-related liver failure is the leading indication for liver transplantation worldwide. Although histologic recurrence is identified in the majority of patients, the spectrum of allograft injury is wide. To date, most studies have focused on the contribution of immunosuppression and viral factors. We hypothesized that the allograft plays a significant role in determining timing and severity of hepatitis C virus (HCV) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable severity of HCV recurrence. Thirty-one HCV-seropositive liver transplant recipients with long-term follow-up were studied. Genomic DNA was extracted from archived donor spleens which corresponded to each patient. We performed polymerase chain reaction amplification, followed by sequencing for two promoter TNF-alpha variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-beta gene (NcoI, TNFc, aa13, and aa26). The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-alpha promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of patients receiving a donor liver homozygous for the TNF1 allele (P = 0.01). There was no correlation between rejection rates and the presence of any TNF-alpha or TNF-beta alleles. TNF-beta polymorphisms within the donor liver did not correlate with severity of HCV recurrence. The donor TNF-alpha promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated graft injury. If the association between this genetic marker (TNF308.2) and disease progression is confirmed, it could improve our understanding of HCV pathogenesis and influence donor selection and patient management.

Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression

Linear IgA disease and chronic bullous disease of childhood are both subepidermal autoimmune blistering diseases. Class I and II major histocompatibility locus (MHC) antigen typing was performed on 60 patients (26 chronic bullous disease of childhood, 34 adult linear IgA disease), and the findings were correlated with the clinical course. The typing was performed using a lymphocyte microcytotoxicity assay, and the results were compared with a reference population of U.K. organ donors. Analysis of the tumour necrosis factor (TNF) locus was performed using sequence-specific oligonucleotides on a dot blot in 51 patients and compared with a random control population and human lymphocyte antigen (HLA) DR3 matched controls. The disease was found to be significantly associated with HLA Cw7 (chi2 = 19.24, P = 0.001), B8 (chi2 = 9.89, P = 0.04) and DR3 (chi2 = 10.47, P = 0.014), all components of the common Caucasian haplotype. There was also a close association between the disease and possession of HLA DR2 or 3 (chi2 = 16.34, P = 0.001). A reduction in the incidence of DR1 and DR4 (alleles carrying the rheumatoid motif) was observed, which is more marked in the children (chi2 = 8.34, P = 0.039). In the childhood group there was an increased frequency of B8, DR3 and DQ2 compared with the adults which included five of 26 who were homozygous for these antigens, a feature not seen in the adults, which may account for the differences seen between the two groups. Possession of HLA B8, DR3 and DQ2 probably facilitates earlier presentation of the disease as there is no evidence from our results that the adults and children differ fundamentally in their MHC associations. The rare TNF2 allele was found in 29 of 51 patients (expected 8.2, chi2 = 18. 3, P = 0.0001). This was more marked in the children (19 of 26). Patients with the TNF2 allele had a longer disease duration (5.3 years TNF2, 3.0 years TNF1).

Gene polymorphism at position -308 of the tumor necrosis factor alpha promotor is not associated with disease progression in multiple sclerosis patients.

Tumor necrosis factor-alpha (TNFalpha) is a pluripotent proinflammatory cytokine and is thought to play an important role in the inflammatory process of multiple sclerosis (MS). A G-->A transition in the TNFalpha promotor at position -308 (TNF2 allele) has been shown to be associated with increased TNFalpha production. This study was designed to detect wether the TNF2 allele is associated with disease progression in MS. We examined the TNFalpha -308 polymorphism with an allelic discrimination PCR to detect the G-->A transition in the genomic DNA of 283 MS patients from Germany and in 72 patients with amyotrophic lateral sclerosis (ALS) and 66 with stroke from the same genetic background who served as controls. Disease severity was defined by the progression index (PI) and by progression to the important clinical landmarks of Extended Disability Status Score (EDSS) 3.5 and 6. In addition, we evaluated the TNFalpha mRNA expression in whole blood with quantitative PCR. No differences were found between the presence of the TNF2 allele in MS, ALS, or stroke patients. Among the MS patients the TNF2 allele was not associated with a certain disease course. No association was found between the accumulation of neurological deficits and progression to clinical landmarks. Although MS patients with the TNF2 allele tended to progress more rapidly from EDSS 3.5 to EDSS 6 this difference was nonsignificant (P = 0.2). Nevertheless, we observed significantly higher TNFalpha mRNA expression in blood cells of stable patients carrying the TNF2-allele in comparison to the group with the wild type (P = 0.024). To examine the effect of genetic background we examined the DNA of 60 MS patients and 20 healthy controls in a Cypriot population of Greek origin. There was a significantly lower frequency of the TNF2 allele in the Cyprus population than in Germans (P = 0.01). No significant differences were found between the frequencies of the TNF2 allele in Cypriot MS patients and controls. Although the TNF2 allele is associated with higher TNFalpha mRNA baseline levels, our data indicate that this allele appears not to contribute to MS susceptibility or severity. In addition our data demonstrate that the TNFalpha -308 polymorphism is segregated differentially in two European populations of different genetic origin.

Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease.

A biallelic G (TNF1 allele) to A (TNF2 allele) polymorphism 308 nucleotides upstream from the transcription initiation site in the tumor necrosis factor (TNF) promoter is associated with elevated TNF levels and disease susceptibilities observed in human subjects. The TNF2 allele is strongly associated with the high-TNF-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF levels and a more severe outcome in infectious diseases, such as cerebral malaria. A number of groups have set out to determine whether the -308 polymorphism could affect transcription factor binding and hence influence TNF transcription and expression levels. Although some studies have failed to show any functional difference between the two allelic forms, others have shown that the -308 polymorphism effected transcription factor binding to the region encompassing -308, with the region in the TNF2 allele showing altered binding characteristics. The -308 polymorphism also has been found by some groups to be functionally significant in reporter gene assays in Raji B cells, Jurkat T cells, and U937 pre-monocytic cells. Up to fivefold differences can be measured between TNF1 and TNF2 allelic constructs when the TNF 3'UTR is present, indicating a role in the expression of the polymorphism. Although controversial, the majority of the data support a direct role for the TNF2 -308 allele in the elevated TNF levels observed in TNF2 homozygotes and HLA-A1, B8, DR3 individuals. Elevated TNF levels due to the -308 polymorphism may alter the immune response such that it confers susceptibility to certain autoimmune and infectious diseases.

Polymorphism in the promoter region of tumor necrosis factor-alpha gene is associated with severe melioidosis

Melioidosis is an important infectious disease endemic in Southeast Asia and the Northern territories of Australia. Septicemic melioidosis, is the leading cause of fatality from community acquired septicemia in northeastern part of Thailand where death often occurs within a few days after hospitalization. The present study was carried out to investigate the polymorphisms of the position −308 promoter region of the TNF-α gene, as well as of the intron 1 of the TNF-β gene in patients with melioidosis compared with normal uninfected controls in the same endemic area. The gene frequency of TNF2 allele was significantly higher in melioidosis patients compared with control subjects ( p = 0.0097, relative risk 2.32). The increase in TNF2 allele in melioidosis patients was found in both heterozygous and homozygous forms. In addition, the increase in TNF2 allele was most apparent in patients who had fatal outcome from septicemic melioidosis ( p = 0.017), but was also observed with lesser degree in other groups of melioidosis patients. However, no difference in the frequency of TNF-β polymorphism the melioidosis patients was observed.

Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study.

Tumor necrosis factor alpha (TNF-alpha) is believed to be a cytokine central to pathogenesis of septic shock. TNF2, a polymorphism within the TNF-alpha gene promoter, has been associated with enhanced TNF-alpha production and negative outcome in some severe infections. To investigate the frequency of the TNF2 allele in patients with septic shock and to determine whether the allele is associated with the occurrence and outcome of septic shock. Multicenter case-control study conducted from March 1996 to June 1997. Seven medical intensive care units in university hospitals. Eighty-nine patients with septic shock and 87 healthy unrelated blood donors. Frequency of the TNF2 allele among patients with septic shock and among those who died and the level of corresponding TNF-alpha concentrations. Mortality among patients with septic shock was 54%, consistent with the predicted mortality from the Simplified Acute Physiologic Score (SAPS II) value. The polymorphism frequencies of the controls and the patients with septic shock differed only at the TNF2 allele (39% vs 18% in the septic shock and control groups, respectively, P =.002). Among the septic shock patients, TNF2 polymorphism frequency was significantly greater among those who had died (52% vs 24% in the survival group, P =.008). Concentrations of TNF-alpha were higher in 68% and 52% with the TNF2 and TNF1 polymorphisms, respectively, but their median values (48 pg/mL vs 29 pg/mL) were not statistically different (P = .31). After controlling for age and the probability of death, derived by the SAPS II score, multiple logistic regression analysis showed that, for the same rank of SAPS II value, patients with the TNF2 allele had a 3.7-fold risk of death (95% confidence interval, 1.37-10.24). The TNF2 allele is strongly associated with susceptibility to septic shock and death due to septic shock.

The tumor necrosis factor-α promoter correlates with progression of primary biliary cirrhosis

Background/Aims: There have been many studies attempting to identify genes that determine susceptibility to primary biliary cirrhosis (PBC), but few studies have attempted to define the genes that modulate the natural history of the disease. There is a biallelic polymorphism, coined TNF1 and TNF2, in the TNFα promoter region at −308. We investigated the relative frequency of the TNF1 and TNF2 alleles in patients with PBC, based on the hypothesis that a polymorphism of the TNFα promoter region may be associated with the rate of progression and prognosis of PBC. Methods: Seventy-one Caucasoid patients with PBC and 133 healthy and unrelated Caucasoid individuals were studied. Genomic DNA was extracted from blood, and the mutation at position −308 of the TNFα gene analyzed by PCR and NcoI digestion. Results: In 71 patients with PBC, 56/71 (78.9%) patients were TNF1/TNF1 homozygotes, 14/71 (19.7%) were TNF1/TNF2 heterozygotes and 1/71 (1.4%) were TNF2/TNF2 homozygotes. In 133 healthy individuals, 109/133 (80.5%) patients were TNF1/TNF1 homozygotes, 24/133 (18%) were TNF1/TNF2 heterozygotes. No control individuals were TNF2/TNF2 homozygotes. The difference between the two groups was not statistically significant ( p=0.3684). However, in patients with TNF1/TNF1 the Mayo score for disease severity was 4.596±0.157 (mean±SEM), compared to 5.637±0.420 for patients with TNF1/TNF2. This Mayo score was significantly higher in patients with the TNF1/TNF2 genotype than those with TNF1/TNF1 ( p=0.0140), with an odds ratio of 4.9. Conclusions: Our data demonstrate that the presence of the TNF2 allele may be associated with a higher Mayo score, and thus with patients in a more advanced clinical stage. These data have both theoretical and clinical implications.

Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis

Background/Aims: Primary sclerosing cholangitis is associated with the HLA haplotypes A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 and DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603. However, the interpretation of these genetic associations is controversial. One explanation may be that HLA-encoded susceptibility is due to other genes carried on these haplotypes such as the HLA class III tumor necrosis factor genes. The aim of the study was to investigate tumor necrosis factor genetics in a large series of well-defined patients.Methods: One hundred and ten HLA genotyped patients and 126 control subjects were studied by polymerase chain reaction genotyping for 3 different tumor necrosis factor gene polymorphisms: −308, −238 and an Nco1 restriction fragment length polymorphism in the lymphotoxin α gene.Results: Overall, 58% of patients had the TNF2 allele, compared with 29% of controls, pc=0.0001. No association was found with either of the other tumor necrosis factor polymorphisms examined. TNF2 was significantly increased in the presence of B8 and DRB3*0101 only, and was independent of DRB1*0301 (pc<0.04). The associations with B8 and TNF2 were stronger than the associations with any of the HLA class II alleles examined.Conclusion: HLA-encoded genetic susceptibility to primary sclerosing cholangitis may be determined by polymorphism within the HLA class III region, in particular with the TNF2 allele.

Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma.

Tumour necrosis factor alpha (TNFalpha) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNFalpha have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNFalpha levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNFalpha production. To investigate the association of differences in asthma-related phenotypes with two biallelic polymorphisms: a G to A substitution at position - 308 of the TNFalpha gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT-alpha*1 and LT-alpha*2 alleles). The regions of interest were amplified from genomic DNA using specific primers and PCR. Dot blot analysis was used for genotyping individuals for the TNFalpha - 308 polymorphism, while restriction enzyme digestion was used for genotyping individuals for the LT-alpha gene NcoI polymorphism. A case-control analysis was then performed on 74 asthmatic and 50 non-asthmatic unrelated children for each polymorphism. The TNFalpha - 308 TNF1 allele was present at a significantly higher frequency in cases than controls (OR= 2.4, P=0.003), and homozygosity for the TNF1 allele was associated with a fivefold increased risk of physician diagnosed asthma relative to the other genotypes (OR = 5.23, P = 0.004). The LT-alpha*2 allele showed similar associations, including an approximately fivefold higher risk of physician diagnosed asthma for LT-alpha*2 homozygotes (OR = 4.89, P = 0.019). Evidence of a significant linear trend in asthma risk across the three genotypes was found for both polymorphisms. These results suggest an important role for the TNFalpha gene or a linked locus in an inherited asthma diathesis.

Analysis of a biallelic polymorphism in the tumor necrosis factor alpha promoter and HIV type 1 disease progression.

The relevance of a TNF-alpha promoter polymorphism, a G-to-A polymorphic sequence at position-308, was examined to test whether variant alleles of TNF-alpha affect susceptibility to infection with HIV-1 and progression to AIDS. Analysis of specimens from cohorts of HIV-1 positive homosexual men demonstrated that 3 of the 32 (9.4%) HIV-1-infected long-term nonprogressors (LTNPs) were homozygous for the uncommon TNF-2 allele compared with 3 of the 196 (1.5%) HIV-1-seronegative blood donors and uninfected homosexual men (p < 0.05). There was no difference in heterozygosity among HIV-1-seropositive or -seronegative groups, although some of the seropositive men heterozygous for the TNF2 genotype were also heterozygous for CCR5delta32. However, no significant association was found between TNF genotypes and time of survival, CD4 slopes, or viral loads when seroincident (n = 109) and seroprevalent cases (n = 442) from the Chicago MACS were analyzed. Functional analysis of lymphocytes from the seronegative group revealed no difference in endogenous or mitogen-induced TNF-alpha production, as well as susceptibility to in vitro HIV-1 infection between different TNF-genotype donors. These data suggest that TNF genotypes do not play a direct role in HIV-1 disease progression; however, they could potentially be part of a multigenic linkage that may be involved in delaying progression to AIDS.

High-producer allele of tumour necrosis factor-alpha is part of the susceptibility MHC haplotype in severe puumala virus-induced nephropathia epidemica.

The biallelic polymorphisms in the tumour necrosis factor-alpha (TNF-alpha) gene promoter region were studied in patients with nephropathia epidemica (NE). The rarer TNF2 allele, associated with a high TNF-alpha producer phenotype, was more frequently found in hospitalized NE patients (42%) than in healthy controls (15%; p=0.0064). The putative role of TNF2 as an independent risk factor for NE is discussed.

Tumor Necrosis Factor- α Gene Polymorphism in Chronic Bronchitis

Airway inflammation is an important pathologic feature in chronic bronchitis, and we hypothesized that individuals with greater inflammatory responses may be more likely to acquire the disease. A polymorphism at -308 position of the tumor necrosis factor-alpha (TNF-alpha) gene has been described, with the rarer allele, TNF2, demonstrated to have higher inducibility in vitro. We investigated the distribution of this polymorphism in a case-control study. The genotype was determined in 42 male patients with chronic bronchitis, 42 sex-, age-, and smoking index-matched control subjects, and 99 random-sampled schoolchildren. We report here that the TNF2 allele is overrepresented in the patient group. The allele frequency of TNF2 is 5.1% in the schoolchildren, 2.4% in the control group, and 19% in the bronchitis group (p < 0.01). Carriage of the TNF2 allele confers a higher risk to the development of chronic bronchitis (odds ratio = 11.1, 95% CI = 2.89-42.57). The results demonstrate the important pathologic role of TNF-alpha in chronic bronchitis and suggest that greater inflammatory response may predispose an individual to this disease.

Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors.

Tumor necrosis factors (TNFs) and heat shock protein 70 (hsp70) are determining factors in immunologic mechanisms to tumor cells. The authors designed a case-controlled study to investigate the potential association of the polymorphisms of TNF-alpha and of hsp70-2 and hsp70-hom genes with malignant tumors. The authors used an allele specific polymerase chain reaction to characterize the variation of the TNF-alpha promotor region in 124 unrelated Tunisian patients with malignant tumors (non-Hodgkin's lymphoma, breast carcinoma, and other tumors) and 106 healthy control subjects. Using polymerase chain reaction and restriction enzyme digestion, polymorphic analysis of hsp70-2 and hsp70-hom genes was performed in patients with non-Hodgkin's lymphoma, in those with breast carcinoma, and in control subjects. Analysis of TNF-alpha polymorphism in patients with malignant tumors and in control subjects demonstrated a high relative frequency of the TNF2 allele in the cancer patients. The relative risk (RR) of lymphoma was especially high in association with TNF1/TNF2 heterozygotes (RR = 6.7; P < or = 0.0001). Polymorphism analysis of the hsp70-2 and hsp70-hom genes in patients with lymphoma and in those with breast carcinoma revealed that these patients had highly significant differences in the genotypic distribution of these biallelic loci compared with the control subjects. Homozygosity for one hsp70-2 allele was significantly associated with lymphoma (RR = 18.2; P < or = 0.0001) and with breast carcinoma (RR = 16.3; P < or = 0.001). Tunisian persons carrying the TNF2 allele may have an increased risk of cancer. In this study, non-Hodgkin's lymphoma and breast carcinoma were significantly associated with polymorphism in hsp70 genes.

A population-based case-control study of the tumor necrosis factor alpha-308 polymorphism in multiple sclerosis.

Tumor necrosis factor alpha (TNF alpha) expression is enhanced in patients with active MS and other inflammatory diseases. A guanine-to-adenine polymorphism at position -308 of the TNF alpha promoter region (the TNF2 allele) is associated with increased TNF alpha expression. We evaluated 110 MS patients derived from an Olmsted County, MN, prevalence study. Three other patient cohorts (autoimmune, serious infectious illness, and other neurologic diseases) and matched controls were derived from a Mayo Clinic DNA bank. We used polymerase chain reaction amplification of specific alleles to screen for the TNF2 allele and to determine zygosity. We found one homozygote and 29 heterozygotes in the MS patients. There was no association between the presence of the TNF2 allele and MS or the other disease categories by matched-pair and group analyses.