TNF-α Genotypes Research Articles

Relevance of IL-1 and TNF gene polymorphisms on interleukin-1β and tumor necrosis factor-α gastric mucosal production

We aimed to evaluate the influence of Helicobacter pylori infection and IL-1/TNF gene polymorphisms on interleukin (IL)-1β and tumor necrosis factor (TNF)-α gastric mucosal production. IL-1β and TNF-α levels in homogenized biopsy specimens taken from the antrum and corpus of 81 patients were measured by enzyme-linked immunosorbent assay. Genomic DNA was typed for the IL1B-511, IL1B+3954, variable number of tandem repeat (VNTR) IL1RN, TNFA-308, TNFA-238, LTA NcoI, and LTA Bsi gene polymorphisms by polymerase chain reaction, restriction fragment length polymorphism, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were determined by Western blot. IL-1β and TNF-α protein levels were significantly higher in the gastric antrum of patients infected with H. pylori compared with uninfected patients [9.54 (5.07–16.28) vs. 4.55 (3.69–8.28) pg IL-1β/mg protein, p = 0.004, and 1.5 (0.7–2.71) vs. 0.63 (0.3–1.26) pg TNF-α/mg protein, p = 0.001]. Among H. pylori-infected individuals, carriers of the IL1RN*2 allele had significantly higher antrum mucosal IL-1β levels than noncarriers [15.97 (9.59–26.6) vs. 10.08 (7.72–13.33), p = 0.008]. No association between gastric mucosal TNF-α levels and genotypes of the TNFA and LTA gene polymorphisms was reported. Our results indicate that the VNTR polymorphism of the IL1RN gene influences IL-1β gastric mucosal production in patients infected with H. pylori.

Cytokine Polymorphisms in the Pathophysiology of Mood Disorders

An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder. Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique. We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048). These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Preliminary Evidence of a Genetic Association Between Tumor Necrosis Factor Alpha and the Severity of Sleep Disturbance and Morning Fatigue

Although fatigue and sleep disturbance are prevalent symptoms in oncology patients and their family caregivers, little is known about the factors that contribute to interindividual variability in symptom severity ratings as well as in their underlying biological mechanisms. In this study, we sought to determine whether a functional genetic variation in a prominent proinflammatory cytokine, tumor necrosis factor-alpha (TNFA-308G>A [rs1800629] promoter polymorphism) was associated with overall ratings of sleep disturbance and fatigue as well as with the trajectories of these symptoms. Over 6 months, participants completed standardized measures of sleep disturbance and fatigue. Multiple linear regression was used to assess the effect of the TNFA genotype and other covariates on mean sleep disturbance and fatigue scores. Hierarchical linear modeling was used to determine the effect of TNFA genotype on the trajectories of these symptoms. Common allele homozygotes reported higher levels of sleep disturbance (p=.09) and morning fatigue (p=.02) than minor allele carriers. Multivariate analyses demonstrated that age and genotype were predictors of both mean symptom scores and the trajectories of these symptoms. Findings provide preliminary evidence of an association between a functional promoter polymorphism in the TNFA gene and the severity of sleep disturbance and morning fatigue in oncology patients and their family caregivers.

Association between TNFA‐308 G/A polymorphism and sensitization to para‐phenylenediamine: a case–control study

Para-phenylenediamine (PPD) and related chemicals are common contact sensitizers, frequently causing allergic contact dermatitis (ACD). The cytokine tumor necrosis factor-alpha (TNF-alpha) plays a key role in contact sensitization. In this case-control study, we evaluated the distribution of variations in the regulatory region of the gene for TNF-alpha (TNFA-308 G/A) in 181 Caucasian individuals with a history of ACD and sensitization to PPD and 161 individuals with no history of sensitization to PPD. The frequency of GA or AA TNFA genotypes was significantly higher in individuals sensitized to PPD than in age- and gender-matched controls giving an odds ratio (OR) of 2.16 (95% confidence interval, CI: 1.35-3.47; P = 0.0016). This relation was even more pronounced when restricting cases to females over 45 years (OR = 3.71; 95% CI: 1.65-8.31; P = 0.0017) vs younger females (less than or equal to 45 years; OR = 2.41; 95% CI: 1.03-5.65; P = 0.044) or males (OR = 1.05; 95% CI: 0.449-2.47; P = 1.0). In addition, a logistic regression model revealed a significant effect for TNFA-308 AA and AG vs GG genotype (point estimate = 2.152; 95% Wald CI: 1.332-3.477). These findings suggest a possible role for the TNFA-308 genetic polymorphism as a susceptibility factor for chemically induced ACD.

Single Nucleotide Polymorphisms in TNF-α, TNFR2 Gene and TNF-α Production in Asian Indians

Polymorphisms in the TNF-α and TNF receptor type 2 (TNFR2) genes in Asian Indians are not well understood. We investigated single nucleotide polymorphisms in the TNF-α 5′-flanking promoter/enhancer region and in exons 6, 9 and 10 of TNFR2 gene by PCR-restriction length polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) techniques, respectively. The results showed single bi-allelic polymorphism in TNF-α (−308G > A) and in TNFR2 exons 6 (676 T > G) and 9 (1176 G > A). Additionally, three bi-allelic polymorphisms (1663 G > A, 1668G > T and 1690C > T) were observed in the exon 10 of TNFR2 gene. The distribution of polymorphic alleles distinctly differed in Aryan and Dravidian Indian communities. The TNF-α and TNFR2 genotype and allele frequencies of Asian Indians stand closer to other Asian populations but distant from Caucasians. Furthermore, TNF-α −308 GA genotype was associated with significantly higher production of TNF-α as compared to GG genotype. These polymorphisms may be related to variation in TNF-α and TNFR2 expression during immune response to various stimuli in Asian Indians.

Gene polymorphisms of TNF-α−308 (G/A), IL-10−1082 (G/A), IL-6−174 (G/C) and IL-1Ra (VNTR) in Egyptian cases with type 1 diabetes mellitus

Background. Type 1 diabetes (T1D) is a genetically conditioned autoimmune disease in which cytokines play an important role.Objectives. To check for the association of polymorphisms of cytokine genes with type 1 diabetes.Subjects. This work included 50 cases with T1D and 98 healthy individuals from the Nile Delta region of Egypt. Cases included 20 males and 30 females with a median age of 25 and range of 15–50 years.Methods. DNA was amplified using PCR with sequence-specific primers for detection of polymorphisms related to tumor necrosis factor (TNF)-α− 308 (G/A), interleukin (IL)-10− 1082 (G/A), IL-6− 174 (G/C), and IL-1Ra (VNTR).Results. Cases with T1D showed significant higher frequency of genotypes of TNF-α− 308 AA (p < 0.001, odds ratio (OR) = 7.91), IL-6-17CC (p < 0.05, OR = 3.36) and IL-1Ra A1A1 (p < 0.05, OR = 3.68) with significant lower frequencies of TNF-α− 308 GA, and IL-1Ra A1A2 genotypes (p < 0.001 and < 0.05, respectively). They also showed significant higher frequency of TNF-α− 308 allele A (p < 0.05, OR = 2.0), IL-1Ra allele A1 (p < 0.05, OR = 2.98) with a significant lower frequency of TNF-α− 308 G allele and IL-1Ra A2 allele (p < 0.05). No significant difference was detected among cases in relation to IL-10− 1082 (G/A) genotypes or alleles nor in relation to age, sex, consanguinity or family history of the disease.Conclusions. Polymorphisms related to TNF-α and IL-1Ra genes may be considered genetic markers for T1D among Egyptians with a potential impact on family counseling and management.

Association of TNFA –308 G/A and TNFRI +36 A/G Gene Polymorphisms with Glaucoma

Objective: TNF-α is one of the most important factors recognized in the pathogenesis of open-angle glaucoma. Therefore, the association of single nucleotide polymorphisms in the TNFRI gene and the promoter region of the TNFA gene with glaucoma susceptibility was investigated in the present study. Method: In total, 223 patients with glaucoma and 202 unrelated controls were genotyped by allele-specific oligonucleotide PCR and PCR- restriction fragment length polymorphism to determine TNFA –308 G/A and TNFRI +36 A/G polymorphisms, respectively. Results: In contrast to TNFRI polymorphisms, the genotypes of TNFA –308 G/A polymorphisms showed a significant difference between patients and controls (p = 0.0025). Of interest, the distribution of TNFA genotypes was significantly different between patients with primary open-angle glaucoma (p = 0.001) or pseudoexfoliative glaucoma (p = 0.001) and controls, while no difference was found when chronic angle-closure glaucoma patients were compared to controls (p = 0.72). Conclusion: In line with studies showing the role of TNF-α in open-angle glaucoma, the results of the present study showed that inheritance of the high producer TNFA –308 A allele might be a susceptibility factor for the development of open-angle glaucoma.

Relationships between C-reactive protein concentration and genotype in healthy volunteers

Polymorphisms of the gene for C-reactive protein (CRP) alter baseline serum CRP concentrations. The impact of polymorphisms of the CRP gene (genotype) on the normal range for CRP concentrations (phenotype) has not been determined. This study evaluated the median serum CRP concentrations in normal subjects stratified for CRP genotype, after adjustment for relevant covariates as well as polymorphisms in tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) genotypes. A total of 423 healthy adults without infectious or inflammatory conditions undergoing phlebotomy for laboratory testing were enrolled in the study. Assays for serum high sensitivity CRP (hs-CRP), IL-6, and TNF-alpha genotypes were measured. The median hs-CRP concentration was 0.96 mg/L (range <0.1-40.15 mg/L). The CRP 1444 C/T heterozygote and homozygote genotype was associated with a significantly higher hs-CRP concentration (p<0.05), even after multivariate analysis controlling for age, gender, body mass index, hypertension, dyslipidemia and obstructive sleep apnea. The CRP 286 C/T/A heterozygote genotype was significant (p<0.05) in the multi-variable analysis, univariately was borderline significant (p=0.052). Selected genetic polymorphisms of the CRP gene are independently associated with higher basal hs-CRP concentrations in healthy adults. Larger studies are needed to perform haplotype analyses and to adequately evaluate the relationship between hs-CRP and genetic polymorphisms with lower allelic frequencies.

Lack of association between the TNF-α -308 (G/A) genetic polymorphism and periodontal disease in Brazilians

This study evaluated the frequency of the tumor necrosis factor-alpha (TNF-alpha) -308 G/A polymorphism in Brazilians with periodontal health (PH = 51), chronic periodontitis (CP = 74) and generalized aggressive periodontitis (GAgP = 38). Human DNA was obtained from mouthwash samples and TNF-alpha genotyping was performed by PCR and RFLP analyses. Differences in clinical and genetic parameters among groups were sought by Kruskal-Wallis, chi(2) and Fisher's exact tests. The allele -308G was detected in 91.7%, whereas the allele -308A was found in 35.4% of all subjects. No significant differences were observed in the frequency of these alleles (chi(2) = 2.610, p > 0.05) and the genotypes G/G, G/A, and A/A (chi(2) = 2.547, p = 0.636) among groups. The data suggest that the TNF-alpha -308 G/A polymorphism is not associated with periodontitis in this Brazilian population.

Absence of Association Between TNF α Polymorphysm and Cerebral Large Vessel Abnormalities in Adults with Sickle Cell Anemia

Purpose: Stroke is a common and serious complication of sickle cell disease (SCD) affecting children as well as adults. Recent reports suggested that promoter region polymorphism in the tumour necrosis factor alpha (TNF-α) gene at position −308 is an important risk factor for large vessel stroke in children with SCD. The role of TNF-α polymorphism in the frequency of magnetic resonance angiography (MRA) abnormalities in adults with SCD is still uncertain. Our objective was to evaluate TNF-α polymorphism in adults with SCD from a tertiary University-based hospital in Sao Paulo, Brazil and correlate them to brain magnetic resonance imaging (MRI) and MRA findings.Casuistic and Methods: The determination of the G-308A polymorphism of the TNF-α gene was performed in forty-nine adult patients with SCD followed in our outpatient clinic. All subjects were evaluated with brain MRI and MRA to determine the presence of previous stroke, arterial tortuosity and intracranial stenosisResults: Thirty-three patients (67.3%) had abnormal brain MRA scans (intracranial stenosis or arterial tortuosity). Eight patients (16.3%) had intracranial stenosis on MRA and 29 (59.2%) showed arterial tortuosity. Forty one patients (83.7%) had the GG TNF-α (−308) genotype and eight had the GA genotype. There were no cases of AA genotype. There was no correlation between homozygosis for the TNF-α (−308) G allele and MRA abnormalities.Conclusion: Although TNF-α (−308) polymorphism has been considered a potential predictor of genetic risk for stroke in children with SCA, we found no association between the polymorphism and large vessel abnormalities in adults with sickle cell disease. (FAPESP: 04/04498-4)

HLA class I and II and TNF-α gene polymorphisms in sarcoidosis patients

IntroductionSeveral factors suggest a genetic predisposition to sarcoidosis, namely the recognition of race as a risk factor and the occurrence of familial clustering of cases. Several studies have reported an association of sarcoidosis and HLA class I and especially class II alleles in different populations. AimHLA class I, class II and TNF-α genotyping in a group of sarcoidosis patients and its relation with clinical presentation and outcome. Material and methodsA total of 104 sarcoidosis patients were included. Clinical presentation, functional, radiology, BAL findings and organ involvement were studied. HLA– A*, -B*, -C*, DRB1*, DQB1* and TNF-α were genotyped by molecular biology methods. DNA was extracted from peripheral blood and PCR-SSP and PCR-reverse hybridisation me-thods were used. Allele frequencies were compared with controls from the same region. The X2 test was used for discrete values and the Kruskal-Wallis test for continuous values. ResultsWhen patients were compared with controls we noticed increased frequencies of B*08 (10.6% vs. 6.1%), O.R.=1.8, C.I.=[1.1;3.1], p=0.02; DRB1*12 (4.3% vs. 1.7%), O.R.=2.63, C.I.=[1.1;6.1], p=0.03. Patients with erythema nodosum have increased frequencies of the alleles DRB1*03 (28% vs. 9.3%), R.R.=2.39, C.I.=[1.5;3.8], pc=0.01 and DQB1*02 (38% vs. 18%), R.R.=2.1, C.I.=[1.3;3.3], pc=0.02. Allele DQB1*03 is decreased in patients with obstructive pattern R.R.=0.53, C.I.=[0.3;0.9], pc=0.05. Allele DRB1*15 is related to restrictive pattern and reduced diffusion capacity (21.1% vs. 6.6%), R.R.=2.46, C.I.=[1.35;4.48], p=0.01 and (18.1% vs. 3.8%), R.R.=1.87, pc= 0.05 respectively. The TNF-α A/A (high) genotype is significantly associated with erythema nodosum (p=0.04). ConclusionsThese data add support to the genetic association of HLA class I and II with sarcoidosis in terms of susceptibility, type of presentation, severity and outcome. Moreover as previously described in other populations, the TNF-α A/A (high) genotype has a significant association with erythema nodosum.

Estudo de polimorfismos genéticos do HLA (classes I e II) e do TNF-α em doentes com sarcoidose

Introduction: Several factors suggest a genetic predisposition to sarcoidosis, namely the recognition of race as a risk factor and the occurrence of familial clustering of cases. Several studies have reported an association of sarcoidosis and HLA class I and especially class II alleles in different populations.Aim: HLA class I, class II and TNF-α genotyping in a group of sarcoidosis patients and its relation with clinical presentation and outcome.Material and methods: A total of 104 sarcoidosis patients were included. Clinical presentation, functional, radiology, BAL findings and organ involvement were studied. HLA– A*, -B*, -C*, DRB1*, DQB1* and TNF-α were genotyped by molecular biology methods. DNA was extracted from peripheral blood and PCR-SSP and PCR-reverse hybridisation methods were used. Allele frequencies were compared with controls from the same region. The X2 test was used for discrete values and the Kruskal-Wallis test for continuous values.Results: When patients were compared with controls we noticed increased frequencies of B*08 (10.6% vs. 6.1%), O.R.=1.8, C.I.=[1.1;3.1], p=0.02; DRB1*12 (4.3% vs. 1.7%), O.R.=2.63, C.I.=[1.1;6.1], p=0.03. Patients with erythema nodosum have increased frequencies of the alleles DRB1*03 (28% vs. 9.3%), R.R.=2.39, C.I.=[1.5;3.8], pc=0.01 and DQB1*02 (38% vs. 18%), R.R.=2.1, C.I.=[1.3;3.3], pc=0.02. Allele DQB1*03 is decreased in patients with obstructive pattern R.R.=0.53, C.I.=[0.3;0.9], pc=0.05. Allele DRB1*15 is related to restrictive pattern and reduced diffusion capacity (21.1% vs. 6.6%), R.R.=2.46, C.I.=[1.35;4.48], p=0.01 and (18.1% vs. 3.8%), R.R.=1.87, pc=0.05 respectively. The TNF-α A/A (high) genotype is significantly associated with erythema nodosum (p=0.04).Conclusions: These data add support to the genetic association of HLA class I and II with sarcoidosis in terms of susceptibility, type of presentation, severity and outcome. Moreover as previously described in other populations, the TNF-α A/A (high) genotype has a significant association with erythema nodosum.Rev Port Pneumol 2008; XIV (6): 727-746

Influence of recipient and donor IL-10, TNFA and INFG genotypes on the incidence of acute renal allograft rejection

Transplantation of renal grafts is an established treatment for renal failure in a variety of medical conditions. Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. Although rejection is mediated by recipient lymphocytes, both donor and recipient factors contribute to the local environment that influences the severity of rejection response. Because cytokines are the main components of immune responses, we evaluate single nucleotide polymorphisms (SNP) of several cytokine genes that may influence the production of a given cytokine and therefore the features of immune reactions. The aim of this study was to determine the impact of the cytokine gene polymorphism of pro and anti-inflammatory cytokines on the development of acute allograft rejection, which could be used in pretransplant patient assessment. Three SNPs including IL-10 (-1082 G/A), TNFA (-308 G/A), and INFG (+874 T/A) were analyzed in 46 patients with acute allograft rejection, 54 patients with stable graft function and their kidney donors by PCR-ARMS method. We are unable to find statistically significant association between any of the studies polymorphisms and clinical outcomes. We have found no evidence to suggest that either recipient or donor cytokines polymorphisms determine the incidence of acute rejection after renal transplantation. Our observation, however, is based on few cases, and this may mask a possible favorable effect. It is recommended that several functionally related genes should be tested in similar studies, since this approach has a higher chance to detect genetic risk factors than the screening of single genetic variants.

Association between tumor necrosis factor-alpha gene promoter polymorphism at position -308 and acne in Turkish patients

Acne is a multifactorial, chronic inflammatory disease of pilosebaceous unit in which cytokines have been implicated in the pathogenesis. Although it is thought to be an inherited disease, there are limited data supporting the relevant genetic elements. Tumor necrosis factor-alpha (TNF-alpha) is one of the proinflammatory cytokines involved in the acne pathogenesis. Several single-nucleotide polymorphisms (SNPs) have been identified in the human TNF-alpha gene promoter. The polymorphism at position -308, which involves substituting guanine (G) for adenine (A) (TNFA-308 G/A) has been linked to increased susceptibility to several chronic inflammatory diseases. The aim of this study was to determine the TNFA-308 G/A polymorphism in acne and to examine whether there is a relationship between this polymorphism and disease susceptibility. Exactly, 113 patients with acne and 114 healthy control subjects were included in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used for analysis of the TNFA-308 G/A polymorphism. We found that the frequency of the TNFA-308 GA genotype was statistically significantly increased in patients compared with healthy controls (P < 0.001). There was no association between TNFA genotypes and severity of acne (P > 0.05). There was also no significant difference between male and female patients. Our results suggest that TNFA-308 G/A polymorphism may contribute to a predisposition to acne in Turkish population.

Tumor necrosis factor α and lymphotoxin α haplotypes in idiopathic recurrent pregnancy loss

To investigate the contribution of the -238G/A and -308G/A tumor necrosis factor (TNF) alpha, and +252A/G lymphotoxin (LT) alpha gene polymorphisms to idiopathic recurrent miscarriage (RM). A retrospective case-control study. Outpatient maternity center. Study subjects comprised 372 RM women and 274 age-matched parous control women. None. The TNFalpha and LTalpha gene variants and idiopathic RM. Higher prevalence of TNFalpha -238A and LTalpha +252G alleles and LTalpha +252G/G genotype and lower frequencies of TNFalpha -308G/A were seen in RM cases. Three-loci haplotype analysis (TNFalpha -308GA/TNFalpha -238GA/LTalpha +252AG) demonstrated significant association between TNFalpha-LTalpha gene variants and RM. Both protective [-308A/-238G/+252A], and susceptible [-308G/-238A/+252G] haplotypes were identified. Mutlivariate regression analysis confirmed the association of -308G/-238A/+252G haplotype with exclusively early RM, after controlling for a number of covariates; no specific TNFalpha and LTalpha genotypes or haplotypes were linked with either late or combined early and late RM. The TNFalpha -238G/A and LTalpha +252A/G, but not TNFalpha -308G/A, polymorphic variants are associated with exclusively early idiopathic RM.

Genetic Polymorphisms of Tumor Necrosis Factor-Alpha Modify the Association between Dietary Polyunsaturated Fatty Acids and Plasma High-Density Lipoprotein-Cholesterol Concentrations in a Population of Young Adults

Background/Aims: Genetic polymorphisms in tumor necrosis factor-α (TNF-α) modify the association between polyunsaturated fatty acids (PUFA) and plasma high-density lipoprotein (HDL) cholesterol in a population with type 2 diabetes. The objective of this study was to determine whether this gene × diet interaction is observed in a diabetes-free population and whether it is due to n–3 or n–6 PUFA. Methods: Subjects (n = 595) were aged 20–29 years and genotyped for the TNF-α –238G>A and TNF-α –308G>A polymorphisms. Diet was assessed using a food frequency questionnaire. Subjects were grouped as having no minor A allele at both the –238 and –308 positions (0/0), or one minor A allele at either the –238 (1/0) or the –308 (0/1) position. Results: TNF-α genotypes modified the association between dietary PUFA and HDL-cholesterol concentrations (p = 0.04 for interaction). Among individuals with the 0/0 genotype, total PUFA was positively associated with HDL-cholesterol in both men (p = 0.008) and women (p = 0.03), and for both n–6 (p = 0.004) and n–3 (p = 0.04) PUFA. However, an inverse relationship was observed among men carrying the 1/0 genotype (p = 0.005). Conclusion: These findings demonstrate that TNF-α genotypes modify the association between dietary PUFA and HDL-cholesterol and provide further evidence that inflammation is involved in the reverse cholesterol transport.

Cytokine gene polymorphism in kidney transplantation — Impact of TGF-β1, TNF-α and IL-6 on graft outcome

Chronic allograft nephropathy (CAN) is one of the main causes of graft loss in renal transplantation. Polymorphisms with functional significance in the promoter and coding regions of cytokine genes have been suggested as a possible factor for graft rejection. The aim of this study was to investigate the impact of cytokine gene polymorphism of pro and anti-inflammatory cytokines on development of CAN in a group of renal transplant patients and donors. Eight single nucleotide polymorphisms (SNPs) including TNFA (−308), TGFB1 (cdns10, 25), IL-10 (−1082, −819, −592), IL-6 (−174) and IFNG (+874) were analyzed in 56 patients with stable graft function (SGF), 10 with CAN and 28 kidney donors by PCR-SSP method. CAN was significantly associated with the recipient TGFB1 cod10 T/T and combination of cods10, 25 T/T G/G genotypes (high producer), (p<0.05). Influence of patient's TNFA genotype correlated with high level of gene expression on the development of CAN was further demonstrated when the patients were stratified according to the HLA mismatches (HLA-DRB MMs). Additionally donor TNFA-308 G/A (high) and IL-6-174 CC (low) genotypes were increased in cases with CAN. No statistically significant differences in distribution of IL-10, IL-6 and IFNG genotypes between recipients with SGF and CAN were found. In conclusion our data suggest that the high producer genotype of profibrogenetic TGF-β1, pro-inflammatory TNF-α and genetically determined low production of immunoregulatory IL-6 cytokine might be risk factors for CAN development.

ASSOCIATION OF TUMOR NECROSIS FACTOR-α–238G&gt;A AND APOLIPOPROTEIN E2 POLYMORPHISMS WITH INTRACRANIAL HEMORRHAGE AFTER BRAIN ARTERIOVENOUS MALFORMATION TREATMENT

We previously reported specific genotypes of polymorphisms in two genes, tumor necrosis factor-alpha (TNF-alpha-238G > A) and Apolipoprotein E (ApoE e2), as independent predictors of new intracranial hemorrhage (ICH) in the natural course of untreated brain arteriovenous malformations. We hypothesized that the risk of posttreatment ICH would also be greater in patients with brain arteriovenous malformations with these genotypes. Two hundred fifteen patients undergoing brain arteriovenous malformation treatment (embolization, arteriovenous malformation resection, radiosurgery, or any combination of these) were genotyped and followed longitudinally. Association of genotype with new symptomatic ICH after initiation of treatment was assessed using Cox proportional hazards adjusted for treatment type, demographics, and established ICH risk factors censored at the time of the last follow-up evaluation or death. The cohort was 48% male and 55% Caucasian, and 52% had an ICH before the initiation of treatment; the mean age +/- standard deviation was 36.6 +/- 17.2 years. Posttreatment ICH occurred in 34 (16%) patients with a median follow-up period of 1.9 years (interquartile range, 1.6 yr). After adjustment, the risk of posttreatment ICH was greater for TNF-alpha-238 AG genotype (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.3-9.8; P = 0.016) and ApoE e2 (HR, 3.2; 95% CI, 1.0-9.7; P = 0.042). Similar trends for the TNF-alpha-238 AG genotype were seen in surgery (HR, 4.2; 95% CI, 0.6-28.8; P = 0.14) and radiosurgery subsets (HR, 3.8; 95% CI, 0.7-19.4; P = 0.11). An effect of ApoE e2 was seen in radiosurgery subsets (HR, 10.9; 95% CI, 1.3-93.7; P = 0.030), but not in surgery subsets (HR, 1.4; 95% CI, 0.3-7.4; P = 0.67). Despite a variety of different mechanisms for posttreatment hemorrhage, these data suggest that the TNF-alpha and ApoE genotypes may contribute common phenotypes of enhanced vascular instability that increase the risk of hemorrhagic outcome.

Genetic polymorphisms of tumor necrosis factor-α modify the association between dietary polyunsaturated fatty acids and fasting HDL-cholesterol and apo A-I concentrations

Background:Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs.Objective:The objective was to determine whether TNF-α genotypes modify the association between dietary PUFA intake and serum lipid concentrations.Design:The study involved 53 men and 56 women aged 42–75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction–restriction fragment length polymorphism for the TNF-α −238G→A and −308G→A polymorphisms.Results:PUFA intake was positively associated with serum HDL cholesterol in carriers of the −238A allele (β = 0.06 ± 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the −238GG genotype (β = −0.03 ± 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the −308A allele (β = −0.07 ± 0.02, P = 0.002), but not in those with the −308GG genotype (β = 0.02 ± 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene × diet interaction was observed when the polymorphisms at the 2 positions (−238/−308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids.Conclusion:TNF-α genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.

A study on the TNF-α system in Caucasian Spanish patients with alcoholic liver disease

Background Tumor necrosis factor-alpha (TNF-α) is thought to be a critical driving force of inflammatory damage in alcoholic liver disease (ALD). We aimed to establish whether there is a correlation between plasma levels of the soluble TNF-α receptors 1 and 2 (sTNFR1 and sTNFR2) and the severity of liver damage in patients with ALD. We also aimed to elucidate whether functionally active polymorphisms in the promoter region of the TNF-α gene modulate the development of ALD. Design We studied 614 Spaniards. Of these, 278 were alcoholics (103 without liver histologic abnormalities, 89 with non-cirrhotic liver disease and 86 with cirrhosis) and 336 were non-alcoholics (115 healthy controls, 114 with non-alcoholic non-cirrhotic liver disease and 107 with cirrhosis unrelated to alcohol). Plasma levels of sTNFR1 and sTNFR2 were determined by ELISA and results were expressed in ng/mL and subsequently converted in log 10. TNF-α gene promoter region polymorphisms at the positions −238, −308 and −863 were assessed by restriction fragment length polymorphisms (RFLPs) on white cell DNA. Differences in plasma sTNFR1 and sTNFR2 levels between groups were compared with the one-way and two-factor analysis of variance test, and Student's t-test. Genotype distribution and allele frequencies in the different groups were compared using the χ 2 test or Fisher's exact test. Results sTNFR1 and sTNFR2 plasma levels were significantly higher in patients with cirrhosis than in those with non-cirrhotic liver disease ( p < 0.001) and individuals without liver disease ( p < 0.001), both in the alcoholic and the non-alcoholic group. Among cirrhotics, sTNFR1 and sTNFR2 levels had a significant positive correlation with the severity of the liver disease, graded with the Child-Pugh's score ( p = 0.003 and p < 0.001, respectively). TNF-α genotype distribution and allele frequencies of the three loci assessed were similar in the groups studied, hence no particular genotype or haplotype could be linked to ALD. Conclusions The TNF-α system is activated in patients with cirrhosis of the liver irrespective of aetiology. TNF-α polymorphisms at positions −238, −308 and −863 are not linked to ALD.