TNF-α Genotypes Research Articles

IL-10 high genotype is protective against acute persistent rejection after lung transplantation

Our previous studies have demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation. The objective of this study was to determine whether cytokine genotypes of TNF-α, IL-10, IL-6, interferon-γ, and transforming growth factor-β were associated with episodes of acute persistent rejection (APR) after lung transplantation (LT).

Cytokine gene polymorphisms moderate responses to respiratory syncytial virus in adults

Immune responses and illness severity during viral upper respiratory infections may be influenced by the local elaboration of cytokines. Cytokine gene polymorphisms moderate immune responses and severity of illness in various inflammatory and infectious diseases. We performed cytokine genotyping on 29 adults experimentally inoculated with respiratory syncytial virus (RSV) to determine whether specific cytokine gene polymorphisms are associated with immune responses or illness severity. DNA was extracted from leukocytes and assayed for TNF-α, IFN-γ, IL-6, IL-10 and TGF-β1 genotypes using polymerase chain reaction–sequence-specific primer technology. Outcomes consisted of baseline and convalescent RSV-specific serum IgG and nasal IgA titers, nasal secretion weights, nasal, throat and general symptom scores, and nasal cytokine protein levels. IFN-γ genotype was directly related with the frequency of subjects having at least a four-fold increase in RSV-specific serum IgG and TNF-α genotype was inversely associated with the frequency of subjects having at least a twofold increase in RSV-specific nasal IgA. Additionally, IL-6 genotype was predictive of certain measures of illness expression, while IFN-γ genotype predicted IL-1 protein levels, and TNF-α genotype predicted IL-6 and IL-8 protein levels in nasal lavage fluids. There were no associations between IL-10 or TGF-β1 and any of the outcome parameters. These results suggest that certain cytokine gene polymorphisms moderate immune responses and illness severity in adults experimentally exposed to RSV.

Cytochrome P4503A5 and TNF-a genotypes are associated with tacrolimus dosing in pediatric heart transplant patients

Cytochrome P4503A5 and TNF-a genotypes are associated with tacrolimus dosing in pediatric heart transplant patients

Association of Tumor Necrosis Factor-α Gene Promoter Polymorphism With Low Attenuation Areas on High-Resolution CT in Patients With COPD

Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-alpha is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position--308 in the promoter of the TNF-alpha gene has been associated with alteration of TNF-alpha secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung. The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score < 11 and those with a visual score > or = 11. A polymerase chain reaction-based assay was developed to determine the TNF-alpha genotype (TNF-alpha-308*1/2) between subjects with high and low visual scores on chest CT scans. The TNF-alpha-308*1/2 allele frequency tended to differ between patients with a visual score < 11 (0.90/0.10) and those with a visual score > or = 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09]. These results indicate that the TNF-alpha-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Association of the tumour necrosis factor alpha -308G/A polymorphism with the risk of diabetes in an elderly population-based cohort.

Ample evidence supports a role for tumour necrosis factor alpha (TNFalpha) in the development of type 2 diabetes and cardiovascular disease. TNFalpha expression was found to be influenced by a -308G/A polymorphism in the promoter of the gene encoding TNFalpha (TNF). We investigated the contribution of this polymorphism to diabetes and cardiovascular mortality in a population-based cohort of 664 subjects aged 85 years and over (Leiden 85-plus Study). The -308G/A TNF promoter polymorphism was associated with the prevalence of diabetes in old age (P = 0.006). The risk of diabetes among subjects homozygous for the A-allele was estimated to be 4.6-fold (95% CI, 1.6-13.3) higher than among subjects homozygous for the common G-allele. The promoter polymorphism did not, however, predict mortality from all causes, cardiovascular diseases, cancer or infectious diseases during a 10-year follow-up period. In addition to the promoter polymorphism, TNFa and TNFc microsatellite genotypes were determined but these polymorphisms were not associated with morbidity or mortality. In conclusion, the -308G/A polymorphism in the TNF promoter is strongly associated with the risk of diabetes but not cardiovascular mortality in old age.

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.

Pro-inflammatory genotypes of IL-1β, TNF-α and IL-10 increase risk of distal gastric cancer but not of cardia or oesophageal adenocarcinomas

Pro-inflammatory genotypes of IL-1β, TNF-α and IL-10 increase risk of distal gastric cancer but not of cardia or oesophageal adenocarcinomas

Pro-inflammatory genotypes of IL-1β, TNF-α and IL-10 increase risk of distal gastric cancer but not of cardia or oesophageal adenocarcinomas

Pro-inflammatory genotypes of IL-1β, TNF-α and IL-10 increase risk of distal gastric cancer but not of cardia or oesophageal adenocarcinomas

Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients

Irreversible acute rejection of the transplanted heart usually has a fatal outcome. Predicting which recipients are most likely to reject might allow closer monitoring and modification of treatment protocols to prevent graft loss. Recipients genetically predisposed to produce more TNF-α are those who suffer the most acute rejection episodes. Here we show that TNF-α genotype is strongly associated with death due to acute cell-mediated heart transplant rejection (Chi-square = 28.57, p < 0.0001). This subgroup of recipients should be given optimally tissue matched transplants and should be treated with the most effective immunosuppressive regimens.

Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis and is also involved in lipid metabolism. Two biallelic polymorphisms within TNF gene locus-TNFA at the position −308 in the promoter region of the TNF gene and TNFB in the first intron of the lymphotoxin-α (LT-α) have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. We studied the association of these polymorphisms within the major histocompatibility complex (MHC) III region with coronary atherosclerosis and its manifestations. The autopsy series comprised 700 Caucasian Finnish men, aged 33–70 years (The Helsinki Sudden Death Study). Coronary stenosis and surface area of atherosclerotic changes (fatty streaks, fibrous plaques, complicated lesions and calcification) were measured and the presence of myocardial infarction and coronary thrombosis recorded. TNFA and TNFB genotypes were determined by the PCR-RFLP technique. The allele frequencies were TNFA1/TNFA2=0.88/0.12 and TNFB1/TNFB2=0.30/0.70. There was a strong linkage disequilibrium between the two polymorphisms. There were no differences in coronary stenosis and in the frequency of old or recent myocardial infarction or coronary thrombosis between men with different genotype status in either locus. Men with TNFA22 or TNFB11 genotype tended to have more fibrous lesions and calcification in their coronary arteries. TNFA and TNFB polymorphisms are unlikely to contribute to progression of atherosclerosis in a way clinically important.

On investigation of markers that may influence alloantibody responses to HPA-1a

In > 99% of cases, HPA-1a antibody production during pregnancy is associated with maternal DRB3*0101 positivity. However, only 35% of HPA-1a neg/DRB3*0101 women produce antibodies (Ab). This study attempted to identify additional genetic marker(s) that may better predict anti-HPA-1a production in these women. Seventy-eight DRB3*0101 pos HPA-1a neg, women (40 HPA-1a Ab pos, 38 Ab neg) with HPA-1a pos infants, were typed for HLA-DRB1*, -B3*, -B4*, -B5*. Results were compared with those from 83 DRB3*0101 pos normal donors. SNaPshot™ was used to test for a polymorphism of the TNF-α locus. The frequency of DRB1*15 was significantly lower in Ab pos mothers (1/40) compared to controls (16/83; P = 0·03), but not compared to Ab neg mothers (6/38; P = 0·07). DRB1*12 was found only in Ab neg mothers (5/38) (controls 0/83; P = 0·02). A study of TNF-α genotype (n = 30, Ab pos; Ab neg; controls) found no difference between the mothers' groups, or mothers and controls. Presence of DRB1*15 or DRB1*12 may lower the likelihood of HPA-1a Ab production. Raised frequency of DRB4* was seen in mothers with affected neonates (13/22) (unaffected, Ab pos 3/11; P = 0·02). DRB4* may increase the odds of HPA-1a alloimmunization. Three NAITP cases due to anti-HPA-1a have been reported (2 local, 1 published), involving mothers DRB3*0101 neg, but DRB4* pos. TNF-α genotype may not predict anti-HPA-1a production in these women. Studies with larger groups would establish the value of these markers in defining women at high risk of HPA-1a alloimmunization.

Variants of Trophic Factors and Expression of Cardiac Hypertrophy in Patients with Hypertrophic Cardiomyopathy

Patients with hypertrophic cardiomyopathy (HCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity, which is partly due to the diversity of causal mutations, genetic background (modifier genes), and probably environmental factors. We determined association of functional variants of tumor necrosis factor (TNF)- α, interleukin-6 (IL6), insulin-like growth factor-2 (IGF2), transforming growth factor- β 1 (TGFB1), and aldosterone synthase (CYP11B2) genes, all previously implicated in cardiac hypertrophy, with the severity of LVH in patients with HCM. Two-dimensional echocardiography was performed and demographic variables were recorded in 142 genetically independent patients. Indices of LVH including interventricular septal thickness (IVST), left ventricular mass index (LVMI), and LVH score were measured/calculated.TNF-α −308G/A, IL6−174G/C, IGF2 820G/A, TGFB1−509C/T, andCYP11B2 −344T/C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were identified by the presence of specific electrophoretic patterns and their distributions were according to the Hardy–Weinberg equilibrium. Demographic variables were not significantly different among the genotypes. Subjects with the AA genotype of TNF-α (n=8) were approximately 13 years younger at the time of clinical diagnosis. Despite a younger age, they had a greater mean LVMI than those with the GG (n=94) or GA (n=33) genotypes (191.8±59.5 v 139.1±47.3 v 132.1±34.3, respectively, P=0.004).TNF-α −308G/A genotypes accounted for 6.0% of variability of LVMI (P=0.002). Mean IVST, LVEDD, and LVH score were not significantly different. Variants of IL6, IGF2, TGFB1, andCYP11B2 were not associated with indices of LVH. The uncommon allele of TNF-α−308G/A polymorphism, known to produce more TNF- α, was associated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicated in cardiac hypertrophy, were not associated with the indices of LVH. These results suggest that TNF-α is a modifier gene for HCM.

Tumour necrosis factor-alpha gene polymorphism: implications in kidney transplantation

In this study we have analysed the TNFA biallelic polymorphism at the −308 position, in 169 kidney recipients that received the graft in a single Italian transplantation facility and we have then correlated the TNFA genotypes with the post-transplant outcome. To assess the cytokine genotypes, a polymerase chain reaction-sequence specific primer (PCR-SSP) methodology has been utilised. By the analysis of the different genotypes, the corresponding TNF-α phenotypes and the level of the TNF-α production, were deduced: the TNF*1/TNF*1 genotype gives a low TNF-α production level, TNF*1/TNF* 2 and TNF*2/TNF*2 genotypes give a high TNF-α production level. Out of the one hundred and sixty-nine patients studied, one hundred and twenty-one recipients (72%) had a low TNF-α producer phenotype, whereas forty-eight (28%) had a high TNF-α producer phenotype. These frequencies were not statistically different from those of the control group. The incidence of acute rejection episodes, vascular damage (grade III° of Banff classification), and serum creatinine levels at 1 month, were significantly greater in high TNF-α producers (P=0.048, 0.031 and 0.007 respectively). The logistical regression model indicated that only the high producer genotype and donor age were significantly and independently correlated with acute graft failure (P=0.02 and P=0.013 respectively). This analysis shows that recipient TNFA polymorphism, previously associated with differential production TNF-α by in vitro studies could be related to the clinical outcome of kidney transplantation.

IL-10, TNF-a and TGF-b genotypes: A role in susceptibility to ulcerative colitis?

IL-10, TNF-a and TGF-b genotypes: A role in susceptibility to ulcerative colitis?

IL-10, TNF-a and TGF-b genotypes: A role in susceptibility to ulcerative colitis?

IL-10, TNF-a and TGF-b genotypes: A role in susceptibility to ulcerative colitis?

Allele typing of human TNFA 5'-flanking region using polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with HLA class I and class II genes in Japanese.

Tumor necrosis factor alpha plays a substantial role in a number of conditions such as inflammation, autoimmunity, insulin resistance and sleep. Three new single nucleotide polymorphisms, -1,031 T/C, -863 C/A and -857 T/C, were recently identified in the upstream 5'-flanking region of TNFA in the Japanese population. In the present study, we developed polymerase chain reaction (PCR)-preferential homoduplex formation assay for the single-step allele typing of TNFA, and determined the genotypes of 271 healthy unrelated Japanese individuals. Four haplotypes, -1,031/-863/-857 TCC, TCT, CAC and CCC, were found to constitute the majority, if not all, of the TNFA alleles of healthy Japanese population. These alleles were designated as TNFA-U01, -U02 -U03 and -U04, respectively, in the order of frequency. Based on HLA-A, -B and -DRB1 genotypes together with TNFA genotypes, multi-locus haplotypes were analyzed. Significant positive associations were observed between TNFA-U01 and A*3303, B*5201, B*4403, B*4601, B*0702, DRB1*1502, DRB1*0101, DRB1*1302, between TNFA-U02 and B*5401, B*3501, DRB1*0405, DRB1*0407, between TNFA-U03 and B*4006, B*4002, DRB1*0803, DRB1*0802, DRB1*0403, DRB1*0901, and between TNFA-U04 and B*4801. Four-locus haplotype estimation revealed that A*3303-B*4403-TNFA-U01-DRB1*1302, A*2402-B*5201-TNFA-U01-DRB1*1502 and A*2402-B*5401-TNFA-U02-DRB1*0405 constitute major extended haplotypes in Japanese. Interestingly, TNFA alleles previously shown to have a higher promoter activity (U02, U03) were found to form haplotypes with certain DRB1 alleles associated with T helper 1 (Th1)-dominant diseases such as rheumatoid arthritis, insulin dependent diabetes mellitus and Crohn's disease in Japanese. In contrast, TNFA allele with a low promoter activity (U01) is in linkage disequilibrium with the DRB1 alleles associated with T helper 2 (Th2)-dominant diseases such as atopic dermatitis and ulcerative colitis. These observations raise the possibility that TNFA upstream promoter region polymorphisms contribute to some of the HLA-disease associations.

TUMOR NECROSIS FACTOR (TNF) GENETIC POLYMORPHISMS CORRELATE WITH INFECTIONS AFTER RENAL TRANSPLANTATION

20 Non-immunosuppressed individuals possessing a NcoI restriction enzyme site in the TNF gene locus produce less TNF-αin vitro and in vivo compared with individuals lacking this restriction site. We have previously shown in liver transplant recipients that this NcoI+ /low TNF genotype is independently associated with increased rates of infection. In this study we performed PCR amplification and RFLP analysis of the TNF locus from 45 renal transplant recipients to determine if, under routine triple immunosuppression, presence of the NcoI site is associated with the occurrence of biopsy proven and treated rejection, culture proven and treated infection, graft loss, and patient death. We controlled for recipient age, sex, maintenance immunosuppression, use of antilymphocyte agents, HLA match and graft ischemia time. Twenty-six recipients typed with the NcoI+ /low TNF genotype while 19 recipients possessed the NcoI /high genotype. Age, sex, donor type, maintenance immunosuppression, use of anti-lymphocyte preparations, graft ischemia time, and year of transplant were evenly distributed among the NcoI+ /low TNF-α and NcoI- /high TNF-α genotypes. There was no difference between the NcoI+ /low TNF-α and NcoI- /high TNF-α genotypes in the occurrence of rejection. In contrast, significantly more patients with the NcoI+ /low TNF-α site developed infections with 1-year infection rates of 50% and 11%, respectively (p=0.01). In a series of bivariate proportional hazards regression models each controlling for TNF genotype and one potential confounder, only donor type and ischemia time were found to be independently associated with infection in addition to TNF genotype. Both donor type and ischemia time served to strengthen the relationship between TNF genotype and infection with odds ratios for infection for those with the NcoI+ /low TNF-α genotype of 6.3 and 6.0, respectively, as compared to an unadjusted odds ratio of 5.4 (Cl 1.2 - 23.8). We conclude that, in individuals genetically predetermined to be low TNF-α producers additional inhibition of TNF-α production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or withdrawal of corticosteroids, which are known inhibitors of TNF-α transcription.

Tumor necrosis factor genetic polymorphisms correlate with infections after liver transplantation. NEMC TNF Study Group. New England Medical Center Tumor Necrosis Factor.

Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory mediator of the immune response to allogenic and infectious stimuli. Non-immunosuppressed individuals possessing a NcoI restriction enzyme site in the TNF gene locus produce less TNF-alpha in vitro and in vivo compared with individuals lacking this restriction site. We performed polymerase chain reaction amplification and restriction enzyme fragment length analysis of the TNF locus from 86 liver transplant recipients to determine if presence of the NcoI site is associated with the frequency of rejection or infection, time to rejection or infection, and patient and graft survival. We controlled for recipient primary diagnosis, age, sex, United Network for Organ Sharing status, year of transplant, type of immunosuppression, use of anti-lymphocyte agents, and graft ischemia time. Fifty-six recipients possessed the NcoI+/low TNF-alpha genotype and 30 were NcoI-/high TNF-alpha genotype. In the first year after transplant, there were no significant differences in the frequency, or time to first rejections or the overall number of rejection episodes between the two genotypes. NcoI+/low TNF-alpha genotype recipients had significantly more infections (1.52 vs. 0.87, P=0.014). In a linear regression, multivariate model controlling for all marginally significant variables, the NcoI+/low TNF-alpha genotype was still associated with significantly more infections (P=0.0031). Patient and graft survival were equal for the two groups. One implication of this study, in individuals genetically predetermined to be low TNF-alpha producers, is that additional inhibition of TNF-alpha production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or withdrawal of corticosteroids.

STABILITY OF THE TOLERANCE PHENOTYPE AFTER WITHDRAWAL OF IMMUNOSUPPRESSIVE DRUG THERAPY: INFLUENCE OF LOCAL AND GENETIC FACTORS INFLUENCING TNFα AND TGFβ EXPRESSION

250 Purpose: To investigate the possible role of a) "low" versus "high" responder TNFα and TGFβ genotype, and b) intragraft expression of these cytokines, on the stability of peripheral tolerance in 2 kidney transplant recipients. Clinical Findings: Both patients JB (FGN; LRD, donor blood transfused) and DS (atrophic kidneys; CAD, OKT3 induction) received a kidney transplant at 16 years of age from a serologically HLA-DR matched and HLA-class I-mismatched donor. Both discontinued all immunosuppressive drug therapy of their own volition 1-2 years after transplant, and both developed focal mononuclear noninvasive infiltrates in their transplant that persisted in biopsy samples obtained at different time points (JB 2 & 9 yr; DS 3 & 4.5 yr) coincident with good renal function (JB 1.6-2.0; DS 1.2-1.4 mg/dl serum Cr). However, while the histology of the DS kidney appears normal 3 and 4.5 years post-op, JB had patchy fibrosis in his transplant biopsy throughout his long (year 2-9) tolerance phase. JB underwent rapid chronic rejection and graft loss between 9 and 10 yr., along with a change from focal to invasive infiltrate pattern. Methods: Genomic DNA samples from peripheral blood of both patients and from the living donor for pt. JB (CL) were analyzed for polymorphisms in the 5′ regulatory region of the TNFα gene (−308), and in the coding region of the TGFβ gene (codon 10 & 25). RNA samples extracted from core biopsy specimens obtained at each time point were analyzed for TNFα and TGFβ gene expression by semi-quantitative RT/PCR using HPLC to separate the PCR product. Results were normalized to the actin RT/PCR signal. Results: As shown in the table, both patients and the LRD donor CL had a high responder genotype for TGFβ. DS had a low responder TNFα genotype, while JB and CL were both TNFα high responders. These genetic differences paralleled the results of biopsy mRNA analysis by RT/PCR. DS had a consistently low TNFα:TGFβ mRNA ratio (avg=.05) in 2 biopsy samples obtained during tolerance. In contrast, JB had a high TNFα to TGFβ expression ratio in both the pre-rejection (9 yr=I) & chronic rejection (10 yr=II) biopsy samples (avg=3.5). Conclusion: The finding of fibrosis early in the tolerance phase in JB, and the absence of fibrosis in the early tolerance phase of DS was correlated with high vs. low TNFα responder genotype, and with TNFα expression within the graft itself. These preliminary findings suggest that pre-existing genetic factors may influence the stability of peripheral tolerance to allografts in humans.Table

Polymorphisms at tumor necrosis factor (TNF) loci are not associated with Chagas' disease.

The aim of this study was to investigate whether the polymorphisms at the TNF loci are associated with Chagas' disease. We determined the TNFA (positions -308, -244 and -238) and TNFB genotypes in a sample of 85 serologically positive chagasic individuals and in 87 healthy controls from a Peruvian population where Trypanosoma cruzi infection is endemic. Patients were subdivided according to the presence (n= 33) or absence (n =52) of chagasic chronic cardiomyopathy, in order to search for genetic differences associated with this pathological condition. No significant differences either between patients and controls or between asymptomatic and cardiomyopathic individuals were observed with respect to TNFA or TNFB polymorphisms when these were considered individually or as extended haplotypes.