TNF2 Alleles Research Articles

Frequency of S and Z alleles for alpha-1-antitrypsin and tumor necrosis factor alpha −308 promoter polymorphism in northeastern Mexico

Diseases characterized by airway inflammation, excessive secretion, and obstruction affect a substantial proportion of the population. Studies for understanding the mechanisms underlying these processes are focused on the initiation and maintenance of inflammation. Polymorphisms on DNA sequence of response mediators such as alpha-1-antitrypsin (AAT) and tumor necrosis factor (TNF) alpha have the capacity to influence presentation of diseases, affecting protein amount and/or functionality, and can be analyzed as disease modulators. The purpose of this study was to analyze AAT S and Z alleles and -308G/A TNF-alpha polymorphism on the northeast Mexico mestizo population to compare the influence of these genes in several diseases. DNA samples from 103 volunteers (healthy group) were tested for modifier gene variants by polymerase chain reaction-RFLP as follows: AAT gene for S and Z alleles and TNF-alpha promoter -308G/A (TNF1/TNF2) alleles. Allele frequency for S and TNF2 alleles were 1.5 and 2.4%, respectively, whereas the Z allele was not detected. This study shows low frequencies of the AAT S and TNF2 alleles, and the Z allele was not found. Correlation studies in the future will allow to determine if these alleles have some influence in the clinical presentation of diverse diseases in this group of people.

TNFα in patients with end-stage heart failure on medical therapy or supported by a left ventricular assist device

Background In the heart elevated levels of TNFα can cause lethal heart failure, like Dilated Cardiomyopathy (DCM). The level of TNFα production is in part determined by promoter gene polymorphisms. We investigated whether the TNFα promoter gene polymorphism is in this way involved in the outcome of end-stage heart failure and predicts whether patients require left ventricular assist device (LVAD) support or can be kept on medical therapy (MT)while awaiting heart transplantation (HTx). As most patients in this study received a heart transplant, the role of the TNFα polymorphisms in transplant rejection was studied as well. Methods and results In twenty nine patients with DCM, 35 patients with Ischemic Heart Disease (IHD; both on MT), 26 patients on LVAD support and 61 cardiac transplant donors TNFα plasma level was detected by EASIA. In both patients groups high levels of TNFα plasma levels was observed however, in patients supported by LVAD this increase was much higher compared to patients on MT. Furthermore, this increase seems to be associated with the TNF 1 allele (‘G’ at position − 308) instead of the TNF2 allele (A at position − 308). The promoter polymorphisms at positions − 238, − 244 and − 308 were observed by polymerase chain reaction and sequencing. Polymorphism at positions − 238, − 244 and − 308 did not show any relevant differences between the groups. However, at position − 308, a trend of a higher incidence of the TNF2 allele (an “A” at position − 308) in DCM patients compared to donors was shown. The distribution of the TNF1 and TNF2 alleles was not different in patients on medical therapy compared to the patients supported by a LVAD. No association was found between patients' TNFα promoter gene polymorphism and rejection. However, patients that received a donor heart with the TNF2 allele developed more rejection episodes, compared to patients that received a donor heart with the TNF1 allele. Conclusion TNFα levels are high in patients with end-stage heart failure on MT, but even higher in patients on LVAD support. These high TNFα plasma levels however, are not correlated with the TNF2 allele but seems to be associated with the TNF1 allele. Furthermore, in HTx the donor TNFα gene seem to play a more important role in severity of acute rejection than that of the patient.

Association of chest radiography findings with host-related genetic factors in patients with nephropathia epidemica

Different host genetic factors causes imbalance in the immune response. The purpose of this study was to establish whether pathological findings in chest radiography are related to the various host-related immunological factors in nephropathia epidemica (NE). Chest radiography findings, human leukocyte antigen (HLA) alleles B8, DR3, B27, genotypes of the genes of tumour necrosis factor alpha (TNFalpha), interleukin -1alpha (IL-1alpha), IL1beta and IL-1 receptor antagonist (IL1RA) were analysed in 114 patients with serologically confirmed acute NE. Both the presence and severity of abnormal NE-related chest radiography findings associated with the B8, DR3 and TNF2 alleles are known to form a frequent extended HLA haplotype in European populations. Pleural effusion showed the strongest association with these genetic factors. Pathological findings in chest radiography are related to host genetic factors in NE. Pleural effusion is a sign of increased capillary permeability, an important feature in NE. Host genetic factors may contribute to increased capillary permeability observed in NE patients.

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of −429T > C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the −429C allele with high hemoglobin A1C levels in diabetic patients

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (−429T > C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE −429C allele. The RAGE −429C allele exhibited highly significant ( p < 0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly ( p = 0.013) higher maximal hemoglobin A1C concentration in the carriers of the RAGE −429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE −429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

Decreased frequency of the TNF2 allele of TNF-α −308 promoter polymorphism is associated with lacunar infarction

Background and purpose Enhanced release of proinflammatory cytokines may contribute to the pathogenesis of stroke. It was examined whether G to A promoter polymorphism in the tumor necrosis factor-α gene at position −308 affects the risk of stroke. Methods We genotyped 336 patients with ischemic stroke and 333 healthy controls for this polymorphism. Patients were divided into different groups based on the Oxfordshire Community Stroke Project (OCSP) or a modified TOAST classification. Distribution of the alleles at −308 G > A promoter polymorphism was determined by PCR–RLFP method. Results Patients with ischemic stroke had a significantly ( p < 0.001) decreased (0.115) frequency of the −308 A (TNF2) allele compared to the healthy controls (0.196). When patients were categorized according to the OCSP classification, it turned out that significant ( p = 0.002) decrease in TNF2 allele frequency (0.065) was restricted to the patients with lacunar infarct (LACI) whereas the frequency of the TNF2 alleles in patients with the other three subtypes (TACI, PACI, and POCI) did not significantly differ from that in healthy controls. Similar results were obtained when the patients were divided according to the modified TOAST classification: the frequencies of the TNF2 allele were 0.068 and 0.140 ( p = 0.010) in the patients with small-vessel and non-small vessel (large vessel infarction or ischemic stroke of other origin) infarction, respectively. The age-adjusted odds ratio of the patients carrying the TNF2 allele to develop lacunar infarct was 0.33 (0.16–0.68) ( p = 0.002) compared to the non-carriers. This difference was also restricted to the male patients. Conclusions Our results suggest that male carriers of TNF2 allele are less susceptible for the development of lacunar subtype of ischemic stroke than the non-carriers.

TNF gene polymorphisms are associated with reduced survival in severe Chagas' disease cardiomyopathy patients

Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-α in the progression of heart failure, and the increased TNF-α plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the −308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction ≤ 40%) according to the presence of the TNF2 promoter allele or the TNFa2 microsatellite allele, both previously associated with high TNF-α production. Multivariate regression analysis (Cox proportional hazards model) revealed the TNF genotype and age of onset of severe CCC as independent predictors of mortality in severe CCC. We showed that patients positive for TNF2 or TNFa2 alleles display a significantly shorter survival time compared to those carrying other alleles; the median survival times were 2.9 and 8 months, respectively (HR adj = 2.28, p = 0.020). We have identified for the first time a genetic factor related to reduced survival in severe Chagas' disease cardiomyopathy. The association of TNF genotype with earlier death in CCC should be taken into account when planning therapeutic intervention.

Increased Risk of Developing Hepatocellular Carcinoma Associated with Carriage of the TNF2 Allele of the -308 Tumor Necrosis Factor-α Promoter Gene

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-alpha at position -308 of the promoter region, which includes TNF1 (-308G) and TNF2 (-308A) alleles, has been found to be associated with susceptibility to various types of cancer. We conducted a study to evaluate the association between this polymorphism and hepatocellular carcinoma (HCC). We recruited 74 HCC patients and 289 healthy controls, and determined their -308 TNF-alpha promoter genotypes through polymerase chain reaction followed by electrophoresis. Carriage of the TNF2 allele was associated with an increased risk of HCC (odds ratio [OR] = 3.5; 95% confidence interval [CI]:[2.1, 6.0]), and a trend toward a significant increase in the risk of developing HCC was observed from TNF1/TNF1, TNF1/TNF2, to TNF2/TNF2 genotypes (p < 0.01). After adjustment for gender, age, and markers of hepatitis B and C, the OR of developing HCC associated with TNF2 allele carriage was 5.3 (95% CI: [2.3, 12.1]; p < 0.01) Carriage of the TNF2 allele is a significant predictor of HCC independent of hepatitis B and C, and therefore it may be used as a biomarker for susceptibility to HCC.

Association of plasma levels of tumor necrosis factor (TNF)-alpha and its soluble receptors, two polymorphisms of the TNF gene, with acute severe pancreatitis and early septic shock due to it.

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in acute severe pancreatitis (ASP). NcoI polymorphism exists in TNF gene promoter and influences TNF-alpha gene transcription. AIMTo determine the predictive value of plasma levels of TNF-alpha and its soluble receptors (sTNFR), TNF-alpha-308 and TNFB polymorphisms on the occurrence of ASP and ASP-associated early septic shock. Genotypes were determined in patients (n = 208) and healthy controls (n = 116) by means of restriction fragment length polymorphism analysis of polymerase chain reaction products. Plasma concentrations of TNF-alpha and sTNFR were measured by ELISA. No significant differences were found in baseline concentrations of TNF-alpha and sTNFR between patients who had early septic shock and those who did not. Baseline TNF-alpha levels did not differ significantly in patients displaying different alleles of the TNF gene. The overall TNF2 allele frequency and TNFB2 allele frequency in patients with ASP were both comparable with those in controls. TNF2 frequency was significantly higher in patients with septic shock than in patients without early septic shock (53.8% versus 22.4%; p = 0.003), as was TNFB2 frequency (88.5% versus 63.2%; p = 0.015). The study found no association between ASP and the two polymorphisms examined, although some associations were found between TNF2 and TNFB2 alleles with the development of early septic shock in ASP. Plasma level of TNF-alpha or sTNFR was of little value in predicting the occurrence of early septic shock in ASP.

El polimorfismo genético del factor de necrosis tumoral alfa como factor de riesgo en patología

Cytokine unbalance is responsible for the pathogenesis of diverse inflammatory, autoimmune and infectious diseases, and Tumor Necrosis Factor Alpha (TNF alpha), among other cytokines, plays a central role. TNF alpha production can be regulated at the transcriptional, post-transcriptional, and translational levels. Variability in the promoter and coding regions of the TNF alpha gene may modulate the magnitude of its secretory response. Up to date, several single nucleotide polymorphisms (SNPs) have been identified in the human TNF alpha gene promoter. One of these, is a guanine to adenine transition at position -308, that generates the TNF1 and TNF2 alleles, respectively. The TNF2 allele is associated to a high in vitro TNF expression, and it has also been linked to an increased susceptibility and severity, for a variety of illnesses, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer disease and cerebral malaria among others. It is also associated with a higher septic shock susceptibility and mortality. The investigation of polymorphisms within the TNF alpha cluster will be important in understanding the role of TNF alpha regulation in specific diseases.

Tumor necrosis factor-alpha promotor polymorphisms and endometriosis

Objective: To explore whether carriage of the mutant tumor necrosis factor TNF2 (G308∗A) and TNFA (G238∗A) alleles in the TNFalpha gene promotor region is increased in women with endometriosis, we determined the respective genotype and allele frequencies in a retrospective case-control study.

Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.

A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene, with a guanine to adenine nucleotide change at position -308, TNF2 is associated with increased TNF-alpha production. TNF2 homozygotes have a higher risk of severe disease and/or death due to cerebral malaria and other infectious diseases. We investigated the impact of this allele on malaria morbidity and mortality in young children who participated in an immuno-epidemiologic cohort study of malaria in an area of intense perennial Plasmodium falciparum transmission in western Kenya. A total of 1,048 children were genotyped. Poisson regression and Cox proportional hazards models were used to determine the relationship between TNF-308 variants and morbidity and mortality. The gene frequencies of the TNF1 and TNF2 alleles were 0.90 and 0.10, respectively. TNF2 homozygosity was associated with pre-term birth when compared with TNF1 homozygotes [relative risk (RR) 7.3, 95% CI, 2.85-18.9, P = 0.002) and heterozygotes (RR 6.7, 95% CI 2.0-23.0, P = 0.008). Among children born prematurely, the TNF2 allele was significantly associated with a higher risk of death in infancy compared with TNF1 (RR 7.47, 95% CI 2.36-23.6). The risk of death was higher among TNF2 homozygotes than among heterozygotes. The TNF2 allele was significantly associated with high density P. falciparum parasitemia (RR 1.11, 95% CI 1.0-1.24). Among low birth weight children, the TNF2 allele was associated with severe anemia (RR 2.16, 95% CI 1.17-4.01) and showed a trend toward a risk for severe malaria anemia (RR 1.99, 95% CI 0.89-4.46). These data suggest that TNF2 is a risk factor for pre-term birth and early childhood mortality and malaria morbidity in children in this region. Further understanding of the pathogenic mechanisms underlying this association is required.

Association of the tumour necrosis factor α −308 but not the interleukin 10 −627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease....

Lack of association between adult asthma and the tumour necrosis factor alpha-308 polymorphism gene.

Tumour necrosis factor (TNF)alpha is a cytokine endowed with potent inflammatory properties that may contribute to airway inflammation in asthma. It has previously been shown that the single base pair polymorphism-308 (G to A substitution) in the promoter of TNFalpha gene results in enhanced cytokine secretion. Whether this polymorphism is associated with the presence of phenotypic expression of asthma is questioned. In this study the relative frequency of TNF1 and TNF2 alleles in a population of adult healthy subjects (n=98) and adult Caucasian asthmatics (n=95) was compared taking into account their disease severity, atopic status and their smoking habit. For the whole group of asthma the genotype frequency for 1/1, 1/2, 2/2 were 67%, 33% and 0%, respectively, and not significantly different from those found in the control group that reached 70%, 28% and 2% respectively (p>0.05). The allele frequencies in asthma were 86% and 14% for TNF1 and TNF2 respectively while the corresponding figures were 85% and 15% in the control group (p>0.05). Furthermore, subdividing asthmatics into severe forced expiratory volume in one second <60% pred), atopic or smoking patients did not show any significant association with this TNFalpha polymorphism. To conclude the polymorphism -308 in the promoter of the TNFalpha gene does not confer a susceptibility to develop asthma nor to grade its severity.

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.

POLYMORPHISMS OF THE GENES OF THE PRO-INFLAMMATORY CYTOKINES IN COELIAC DISEASE: ASSOCIATION OF THE IL1A2 AND TNF2 ALLELES

111 The genes of the cytokines regulating the inflammatory reactions (e.g. IL-1a and IL-1b, TNF-a and TNF-b and IL-1 receptor antagonist (IL-1RA)) are polymorphic and it is known that certain alleles of these loci have a role in the genetic susceptibility in several autoimmune or inflammatory diseases. In the promoter of the TNF-a gene, at the position-308 relative to the transcriptional start site, there is a biallelic base exchange polymorphism defining the alleles TNF1 and TNF2. The frequency of the more rare allele, TNF2, is known to be increased in coeliac disease (CD), but as the TNF gene locates within the HLA complex, its role as an HLA-independent factor has been difficult to assess. Now we have analyzed the polymorphisms of the IL-1 gene complex in CD. In the IL-1a gene there is one base exchange polymorphism at the position-889(alleles IL1A1 and IL-1A2) and in the IL-1b two, at the positions-511 and+3953. The intron 2 of the IL-1RA gene contains variable numbers of 86-bp tandem repeats. In the 50 CD patients analyzed, the frequencies of all the alleles of these loci were similar to those found in 50 healthy blood donors. In accordance with the previous studies, the frequency of TNF2 was increased(0.49 in CD patients vs. 0.19 in the controls). However, when the associations between the different alleles were analyzed, it was observed that in CD patients, but not in controls, the IL1A2 and TNF2 alleles were strongly associated. These data suggest that polymorphisms of the cytokine genes have an influence on the genetic susceptibility to CD, but this effect may require co-operation between different alleles.

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.

Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease.

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathophysiology of sepsis. Levels of TNF-alpha are directly correlated with severity in meningococcal disease (MD). A polymorphism in the promoter region of the TNF-alpha gene is associated with differences in the secretion of TNF-alpha. The TNF2 allele is associated with higher constitutive and inducible levels of TNF-alpha secretion than is the TNF1 allele. To investigate whether possession of the TNF2 allele is associated with severity in MD, the frequency of TNF1 and TNF2 alleles in 98 children with MD was compared. There were more deaths among children who had the TNF2 allele (P = .03; relative risk [RR], 2.5; 95% confidence interval [CI], 1.1-5.7) than in those who did not. There was also an increased risk of severe disease in children with the TNF2 allele (P = .02; RR, 1.6; 95% CI, 1.1-2.3). Possession of the TNF2 allele predisposes to a worse outcome in children with meningococcal infection.

TNF2, a polymorphism of the tumour necrosis-alpha gene promoter, is a component of the celiac disease major histocompatibility complex haplotype.

Celiac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF-alpha, which encodes the cytokine tumor necrosis factor-alpha which has a broad range of pro-inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF-alpha could be important in the pathogenesis of MHC-associated immune disorders. A TNF-alpha variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC-linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLA A1-B8-DR3-DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE +/- 0.0490) in CD, compared to 0.1635 (+/- 0.0362) in a control sample (p < 10(-6)). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA-DQB1*0201 (frequency = 0.7791 +/- 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.

Polymorphism of the tumor necrosis factor genes in patients with dermatitis herpetiformis.

In 18 patients with dermatitis herpetiformis (DH) of whom 16 were HLA-DR3 positive and 14 had the HLA-B8, -DR3 haplotype, the frequencies of known mutations of the tumor necrosis factor alpha (TNF-alpha) and TNF-beta genes were investigated using restriction fragment length polymorphism analysis and the single-strand conformational polymorphism technique. In DH, the phenotype frequency (28%) and allele frequency (0.58) of the rare TNF-beta allele TNFB*1 were significantly increased (normal control 12.4% and 0.37). For the TNF-alpha promoter/enhancer polymorphism, the rare allele TNF2 was more frequent in DH patients (11%, 0.47) compared to controls (2%, 0.16). Since functional studies have associated the rare TNFB*1 and TNF2 alleles with a higher secretion of TNF upon activation in vitro, the predominance of these two 'high-response' TNF alleles in DH patients may represent a genetic basis for the chronic inflammatory response in the skin and mucosal tissues of patients with DH.