TNF-α Allele Research Articles

Effect of the TNF-α–promoter polymorphism on cardiac allograft rejection

Background A polymorphism exists in the tumor necrosis factor α (TNF-α) promoter (position −308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-α production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. Methods We prospectively analyzed 57 subjects (aged 54 ± 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 ± 605 days) and the frequency of allograft rejection (biopsy Grade ≥2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. Results The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 ± 11 days; Group B, 20 ± 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). Conclusion The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.

Tumor necrosis factor-alpha allele lymphotoxin-alpha+250 is associated with the presence and severity of placental inflammation among preterm births.

Histologic inflammation of placenta has been associated with increased risk for bronchopulmonary dysplasia and periventricular leukomalacia among preterm infants. Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the regulation of inflammation. Some alleles of TNF (LT-alpha+250, TNF-alpha-308, and TNF-alpha-238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or involving the immune system. To determine whether alleles of TNF-alpha affect the risk and/or the severity of chorioamnionitis, we examined the placentas of 101 preterm births (birth weight <or=1250 g) for the presence of inflammation. Maternal and fetal chorioamnionitis (MCA and FCA, respectively) were graded for severity and staged for location of inflammatory infiltrate. Analysis for TNF-alpha alleles was done using PCR-restriction fragment length polymorphism technique on DNA extracted from infants' whole blood. MCA and FCA were seen in 45 and 38 placentas, respectively (p = 0.64). Genotypes of TNF-alpha-308 did not affect the development or the severity of placental inflammation. However, the AA genotype of LT-alpha+250 occurred more often when MCA and FCA were present compared with placentas without inflammation (p = 0.016 and p = 0.007, respectively). The GA genotype of TNF-alpha-238 was more common in placentas with severe MCA than with mild MCA (p = 0.015). The number of A alleles of LT-alpha+250 (GG = 0, GA = 1, AA = 2) correlated directly and significantly with grades and stages of MCA and FCA (p < 0.05). The AA genotype of LT-alpha+250 is associated with the development of chorioamnionitis among preterm births. The A allele of LT-alpha+250 seems to worsen the degree of placental inflammation.

Polymorphisms in the TNFA gene promoter region show evidence of strong linkage disequilibrium with HLA and are associated with delayed neutrophil engraftment in unrelated donor hematopoietic stem cell transplantation.

Sustained myeloid engraftment is an important determinant of outcome in hematopoietic stem cell transplantation (HSCT). Human tumor necrosis factor (TNF)-alpha is encoded by a gene, TNFA, located in the class III region of the major histocompatibility complex on chromosome 6, flanked by the human leukocyte antigen (HLA) class I and II regions. A number of polymorphisms in the promoter region of the TNFA gene have been associated with increased production of TNF-alphain vivo. Additionally, raised TNF-alpha levels have been reported to have a detrimental effect on the outcome in HSCT, in particular on early complications such as acute graft vs host disease, failure to engraft, and transplant-related mortality. There is evidence of linkage disequilibrium (LD) between TNFA promoter polymorphisms and extended HLA haplotypes. We have genotyped 73 cell lines and 189 donor/recipient pairs (undergoing HSCT) for their TNFA polymorphism, all of which had been well characterized with respect to their HLA genes. We found evidence of strong LD between HLA genes and TNFA; however, there was also evidence for recombination events having taken place, as we found that a number of transplant pairs who were matched for their HLA haplotypes were not matched for their TNFA alleles. We analyzed early outcomes in the transplant recipients and found a significant delay in engraftment in those pairs where both donor and recipients possessed an AG allele (associated with higher TNF-alpha levels). Our results suggest a functional effect of TNFA polymorphisms on myeloid engraftment in unrelated HSCT.

Lack of association of TNFα gene polymorphisms and recurrent pregnancy loss in Caucasian women

The tumor necrosis factor alpha (TNFα) gene plays an important role in immunology and inflammation. Variant alleles of TNFα are associated with altered RNA and serum protein levels in humans. Conflicting results have been obtained regarding the role of TNFα during pregnancy and recurrent pregnancy loss (RPL). This study investigated the relationship between RPL and two polymorphisms in the promoter of the TNFα gene (TNFα −308 and −863). Genotyping was performed in 168 RPL women and 212 ethnically matched healthy individuals. In addition, we performed analysis of TNFα serum protein levels. We demonstrate that neither the polymorphism −308 nor the polymorphism −863 of the TNFα gene is associated with RPL in Caucasian women. In addition, we did not find any association between TNFα serum levels and the occurrence of RPL in a subset of 36 RPL women and 36 healthy individuals. We conclude that TNFα polymorphisms and resting blood TNFα levels do not correlate with the propensity to recurrent pregnancy loss in Caucasian women.

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

Background—Tumor necrosis factor‐α (TNF‐α), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position −308 and TNFB at +252) may influence TNF‐α production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF‐α production. We investigated the genotypes associated with increased TNF‐α production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response.Methods—TNF gene polymorphisms were analyzed by multiplex fluorescent solid‐phase minisequencing in 86 CABG patients. Plasma concentrations of TNF‐α, IL‐6 and C3a and C‐reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF‐α producers.Results—Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2 = 0.84/0.16 and TNFB1/TNFB2 = 0.32/0.68. Pre‐ and postoperative levels of TNF‐α, IL‐6, C3a and CRP did not differ significantly between genetically high and low TNF‐α producers.Conclusions—The frequency of high TNF‐α producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF‐α gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

Background—Tumor necrosis factor‐α (TNF‐α), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position −308 and TNFB at +252) may influence TNF‐α production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF‐α production. We investigated the genotypes associated with increased TNF‐α production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response.Methods—TNF gene polymorphisms were analyzed by multiplex fluorescent solid‐phase minisequencing in 86 CABG patients. Plasma concentrations of TNF‐α, IL‐6 and C3a and C‐reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF‐α producers.Results—Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2 = 0.84/0.16 and TNFB1/TNFB2 = 0.32/0.68. Pre‐ and postoperative levels of TNF‐α, IL‐6, C3a and CRP did not differ significantly between genetically high and low TNF‐α producers.Conclusions—The frequency of high TNF‐α producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF‐α gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.

Influences of IL-1B, IL-1RN, TNFA, AND TNFB alleles on chronic HBV infection and perinatal infections of hepatitis B virus after immunoprophylaxis

Influences of IL-1B, IL-1RN, TNFA, AND TNFB alleles on chronic HBV infection and perinatal infections of hepatitis B virus after immunoprophylaxis

Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population.

In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.

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.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis.

To investigate polymorphisms in the genes for tumour necrosis factor alpha (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement. One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions -308, -238, +488), IL10 (-1082, -819, -592) and in the 3'-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions. HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P<0.05) and was associated with younger age of onset of psoriasis (P<0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele -238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele -238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA -238A alleles (23/23) in patients with PsA were HLA-Cw*0602-positive (P<0.0001). An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA -238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted.

TNFα−308A associated with shorter intervals of Plasmodium falciparum reinfections

A mutation at position -308 of the tumor necrosis factor alpha (TNF-308A) gene promoter has previously been associated with particular manifestations of infectious and non-infectious diseases. In a longitudinal study on malariological parameters in Gabon, TNF promoter variants of 98 children initially presenting with severe Plasmodium falciparum malaria, followed by a total of 504 reinfection events within 52 months, and 100 children initially presenting with mild malaria followed by a total of 342 reinfections were analyzed. Symptomatic P. falciparum reinfections occurred more quickly (median 11 weeks) in carriers of the TNF-308A allele, with severe malaria at enrollment, compared to carriers of other TNF promoter variants (median 16 weeks). The results show that this particular TNF promoter allele increases the risk of reinfection with the malaria parasite P. falciparum.

Polymorphism of the cytokine genes and IgA nephropathy

IgA nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Cytokine gene polymorphisms regulate cytokine production and play a role in immune and inflammatory responses; these immunological responses thus are possibly involved in the etiology and pathogenesis of IgAN. We studied by polymerase chain reaction (PCR) polymorphisms of important cytokine genes of inflammation interleukin-1 (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) in 167 patients with IgAN and 400 healthy blood donor controls. IgAN patients had been followed up for 6 to 17 (median 11) years from renal biopsy. Carriage of the IL-1beta allele 2 (IL1beta2) or IL-1Ra allele 2 (IL1RN*2) was associated with an increased risk of IgAN. These alleles were highly linked and the odds ratio (OR) of IgAN for carriage of both alleles was 1.8 (95% confidence interval 1.2 to 2.6; P = 0.002). Carriage of the TNF-alpha allele 2 (TNF2) was associated with a decreased risk of IgAN (OR 0.5, range 0.3 to 0.7; P = 0.001). The risk of IgAN was found to be highest in those carrying IL1beta2 and IL1RN*2 but not TNF2 as compared to those who did not carry both of these IL-1 cluster genes and were carriers of TNF2 (OR 5.0 (2.4-10.3); P < 0.001). None of the polymorphisms studied was associated with poor prognosis. Carriage of IL1beta2 and IL1RN*2 together with non-carriage of TNF2 is associated with increased susceptibility, but not with a prognosis of IgAN.

Relationship of tumour necrosis factor alpha gene polymorphisms and neuropsychiatric lupus.

Systemic lupus erythematosus (SLE) is a multisystem disorder which appears to be influenced by genetic make-up. In this study we determine allele frequency and genotype distribution of TNFalpha polymorphisms in two populations of SLE patients (with and without neuropsychiatric manifestations) in order to determine whether the rare allele (TNF2) confers susceptibility for neuropsychiatric disease in SLE. Patients with SLE were retrospectively reviewed to determine presence (n = 17) or absence (n = 47) of documented neuropsychiatric manifestations attributable to SLE. The DNA from these patients was extracted from peripheral blood mononuclear cells, and PCR amplification, NcoI enzyme digestion and 10% polyacrylamide gel electrophoresis were performed to define the different TNFalpha alleles. Two alleles were demonstrated, TNF1 (wild-type) and TNF2 (rare type), with three possible genotypes, TNF1,1, TNF1,2 and TNF2,2. A frequency of 24% was found for the TNF2 patients with neuropsychiatric involvement and was not statistically different to a frequency of 28% found in SLE patients without neuropsychiatric manifestations. The TNF-2 allele does not confer susceptibility for neuropsychiatric manifestations in SLE patients.

Microsatellite DNA markers from HLA region ( D6S105, D6S265 and TNFa ) in autochthonous Basques from Northern Navarre (Spain)

Background : The extent of the genetic polymorphism of the HLA complex is becoming well characterized in Basque population and their subpopulations. This level of knowledge mainly concerns HLA class I loci. However, Basque population surveys dealing with HLA class II genes and/or microsatellites in the HLA region are still very scarce. Aim : The population genetics of three highly polymorphic short tandem repeat (STR) loci, D6S105, D6S265 and TNFa, from HLA region has been analysed in autochthonous (indigenous) Basques from Northern Navarre (Spain). The same blood samples have been typed for HLA class II genes from DQ/DR/DP regions and some findings from that information can be found therein. Subjects and methods : Blood samples were taken from 107 unrelated autochthonous Basques from Northern Navarre. The criterion used to define Northern Navarrese identity was that of three generations of Basque surnames and birthplaces. Results : The main features observed in Navarrese Basques were the rather high frequencies of alleles D6S105*4 and D6S265*7. A novel allele has been detected at the D6S265 locus (13: 145 bp). The most frequent haplotype was D6S105*8-D6S265*4 with a highly significant linkage disequilibrium being presented. The high frequency of allele TNFa*1 in Basques is noteworthy and this characteristic is not shared by other European populations, where TNFa*1 is absent or shows negligible values. The multidimensional scaling analysis (MDS) for TNFa allele frequencies has shown a high variability among populations and that alleles TNFa*1 ( F ST = 0.0615) and TNFa*12 ( F ST = 0.0424) seem to have significant influence over the spatial population configuration. TNFa*2 showed the lowest FST value (0.0077) because of its conspicuous homogeneous distribution all over the European populations. Conclusions : Findings shown here on HLA microsatellites and their relationships with other HLA class I and class II genes in Basques can be helpful for those studies mainly addressed at detecting associations between HLA genes and diseases in the Basque area as a whole, and particularly in its autochthonous population, settled there since remote times.

Influence of tumor necrosis factor-α gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation

Background Tumor necrosis factor-α (TNF-α) has been implicated in cardiovascular disease. Polymorphism of the TNF-α gene promoter region (position -308) influences an individual’s production of TNF-α. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-α have been found in recipients with cardiac transplant vasculopathy and because TNF-α blockade can prevent the disease in rabbits, we investigated the effect of TNF-α promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients Methods Using sequence-specific primers to the TNF-α gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-α genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. Results We found that 31.9% of recipients and 27.0% of donors were high TNF-α producers. The presence of the high-producing TNF-α allele led to an earlier diagnosis of vasculopathy; 3.42 years (± 91.3 days) vs 3.84 years (± 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (± 87.3 days) vs 3.78 years (± 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-α polymorphism had no effect on the freedom from vasculopathy when considering either recipient ( p = 0.99) or donor ( p = 0.86) TNF-α genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. Conclusions Polymorphism at position -308 in the promoter region of the TNF-α gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.

Autoimmune hepatitis in Brazilian patients is not linked to tumor necrosis factor α polymorphisms at position −308

Background/Aims : Susceptibility to autoimmune hepatitis (AIH) has been linked to different HLA-DR antigens. Recently, AIH type 1 was associated with polymorphisms in the tumor necrosis factor α gene promoter (TNFA) at position -308. In this respect, the frequency of the TNFA*2 allele, in linkage disequilibrium with HLA-DRB1*0301, was shown to be significantly increased in whites with AIH type 1. The aim of this study was to assess the role of TNFA alleles in conferring susceptibility to AIH, studying a population where the disease is not primarily associated with HLA-DRB1*03. Methods : The determination of HLA-DRB1 and TNFA alleles was performed in 92 patients with AIH type 1, 29 subjects with AIH type 2 and 83 healthy controls by polymerase chain reaction-based techniques. Results : The distribution of TNFA alleles was similar in patients with AIH types 1 and 2, when compared with controls. In addition, the TNFA*2 allele was identified in patients carrying HLA-DR antigens other than HLA-DRB1*03. Interestingly, higher gammaglobulin levels were observed in TNFA*2 positive patients. Conclusions : Our data indicate that susceptibility to AIH remains primarily linked to the HLA-DRB1 locus, and suggest that the association of AIH with TNFA*2 previously observed in whites might be secondary to a linkage disequilibrium with HLA-DRB1*0301.

Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls.

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.

Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer's lung patients.

Hypersensitivity pneumonitis (HP) represents an immunologic reaction of the pulmonary parenchyma to an inhaled agent. Since tumor necrosis factor (TNF)-alpha is thought to be involved in the pathogenesis of HP, and polymorphisms in the TNF genes have been associated with variations in the production of TNF-alpha, we investigated the serum bioactivity and genotype of TNF in HP. TNF bioactivity was measured after hay dust challenge in eight patients with farmer's lung (Group A) and in 12 healthy, sensitized (antibody-positive) controls (Group B). Genotyping for the -308 TNF-alpha promoter polymorphism and the TNF-beta intron 1 gene polymorphism was performed in 20 patients with farmer's lung, 25 patients with pigeon breeder's lung, and 216 controls. TNF bioactivity increased in Group A at 4 to 10 h after hay dust challenge, but not in Group B (p < 0.05). The frequency for the TNFA2 allele, a genotype associated with high TNF-alpha production in vitro, was significantly higher in farmer's lung patients (frequency [f] = 0.43, p = 0.0012) than in controls (f = 0.19) or patients with pigeon breeder's lung (f = 0.16). Genotyping for TNF-beta revealed no significant abnormalities. Thus, increased production of TNF-alpha after hay contact, and a genetic predisposition to TNF-alpha production, are implicated in the pathogenesis of alveolitis in farmer's lung.

TNFA gene: the -308 promoter polymorphism in migraine

Molecular analysis of TNFA alleles in Italian subjects affected by migraine was performed in order to define the involfement of HLA region genes in migraine. No statistically significant differences in TNFA allele distribution between patients and controls were observed.