Tumor Necrosis Factor-α Gene Polymorphisms Research Articles

Tumor Necrosis Factor-α Gene Polymorphisms and Risk of Oral Cancer: Evidence from a Meta-analysis

Numerous studies have been conducted regarding association between TNF-α and oral cancer risk, but the results remain controversial. The present meta-analysis is performed to acquire a more precise estimation of relationships. Databases of Pubmed, the Cochrane library and the China National Knowledge Internet (CNKI) were retrieved until August 10, 2013. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated with fixed- or random-effect models. The heterogeneity assumption was assessed by I-squared test. Among the eight included case-control studies, all were focused on TNF-α-308G>A and four also concerned the TNF-α-238G>A polymorphism. It was found that oral cancer risk were significant decreased with the TNF-α-308G>A polymorphism in the additive genetic model (GG vs. AA, OR=0.19, 95% CI: [0.04, 1.00], P=0.05, I2=68.9%) and the dominant genetic model (GG+GA vs. AA, OR=0.22, 95% CI: [0.06, 0.82], P=0.03, I2=52.4%); however, no significant association was observed in allele contrast (G vs. A, OR=0.70, 95% CI: [0.23, 2.16], P=0.54, I2=95.9%) and recessive genetic models (GG vs. GA+AA, OR=0.72, 95% CI: [0.33, 1.57], P=0.41, I2=93.1%). For the TNF-α-238G>A polymorphism, significant associations with oral cancer risk were found in the allele contrast (G vs. A, OR=2.75, 95% CI: [1.25, 6.04], P=0.01, I2=0.0%) and recessive genetic models (GG vs. GA+AA, OR=2.23, 95%CI: [1.18, 4.23], P=0.01, I2=0.0%). Conclusively, this meta-analysis indicates that TNF-α polymorphisms may contribute to the risk of oral cancer. Allele G and the GG+GA genotype of TNF-α- 308G>A may decrease the risk of oral cancer, while allele G and the GG genotype of TNF-α-238G>A may cause an increase.

Tumor Necrosis Factor-α Gene Polymorphisms in Korean Patients With Recurrent Spontaneous Abortion

The objective of this study was to investigate the contribution of the tumor necrosis factor-α (TNF-α) gene polymorphisms to recurrent spontaneous abortion (RSA). The study participants consisted of 357 Korean women with RSA and 236 fertile women controls. Four TNF-α gene variants of all participants were analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. The TNF-α -1031T>C and TNF-α -238G>A variants increased the risk of RSA TNF-α -1031TC+CC; adjusted odds ratio [AOR], 2.292; 95% confidence interval [CI], 1.547-3.395; P < .001; TNF-α -238GA+AA; AOR, 2.327; 95% CI, 1.038-5.217; P = .040), and these data were not different in a stratified analysis according to the number of consecutive spontaneous abortions. Also, the mutant genotypes of TNF-α -1031 and TNF-α -238 showed synergistic effects on increased RSA risk (-1031TC+CC/-238GA+AA; AOR, 4.054; 95% CI, 1.520-10.812; P = .005). In haplotype analysis, there were similar trends of data for combination analysis. In conclusion, the TNF-α -1031T>C and TNF-α -238G>A variants are possible genetic risk factors for RSA.

Tumor Necrosis Factor-α Gene Polymorphism Relationship to Seminal Variables in Infertile Men

To assess the tumor necrosis factor (TNF)-α gene polymorphism relationship with seminal variables in fertile men (N) and those with asthenozoospermia (A), asthenoteratozoospermia (AT), and oligoasthenoteratozoospermia (OAT). A total of 50 infertile men without a female factor who were attending a fertility clinic and 48 fertile men were randomly screened for semen analysis, analysis of the TNF-α promoter region for polymorphism, seminal caspase-9, acrosin activity, α-glucosidase, and reproductive hormones. The TNF-α GG genotype was present in 83.9%, 72.7%, 66.7%, and 59.5%, the TNF-α AA genotype in 3.2%, 6.8%, 10.4%, and 11.9%, and TNF-α AG genotype in 12.9%, 20.5%, 22.9%, and 28.6% in the N, A, AT, OAT groups, respectively. The occurrence of A allele was significantly greater among infertile patients than among fertile controls (21.6% vs 9.7%; odds ratio 0.388, 95% confidence interval 0.2 to 0.75, P = .005). Men with the TNF-α AA genotype demonstrated a significant decrease in the sperm count, sperm motility, normal sperm morphology, acrosin activity, and seminal α-glucosidase and a significant increase in seminal caspase-9 compared with those with the TNF-α GG genotype. This single nucleotide polymorphism in the TNF-α(-308) gene was associated with significantly increased seminal caspase-9 and a significantly decreased sperm count, sperm motility, normal sperm morphology, acrosin activity, and seminal α-glucosidase.

Gene Polymorphisms of Interleukin-10 and Tumor Necrosis Factor-α Are Associated with Contrast-Induced Nephropathy

Background/Aims: Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired acute renal failure. However, the pathogenesis of CIN remains unclear. This study evaluated the role of anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) gene polymorphisms as CIN susceptibility markers after percutaneous coronary intervention (PCI). Methods: Four IL-10 tag SNPs (rs1554286, rs3021094, rs3790622, rs1800896) and three TNF-α tag SNPs (rs1799964, rs1800630, rs1800629) were analyzed by MALDI-TOF mass spectrometry in 53 CIN patients and 455 control subjects. Serum IL-10 and TNF-α were detected using ELISA. Results: When compared to controls, the CIN patients showed increased frequencies of CC (rs1554286) and AG+GG (rs1800896) genotypes in IL-10 and GA+AA (rs1800629) genotype in TNF-α (OR = 2.24 (1.13–4.44), p = 0.018; OR = 2.61 (1.30–5.26), p = 0.005, and OR = 2.11 (1.08–4.09), p = 0.025, respectively). Baseline serum IL-10 levels in CIN patients were significantly lower (1.02 ± 1.14 vs. 2.78 ± 4.73 pg/ml, p = 0.008). Patients with CIN had a higher rate of decline in renal function than those without CIN (0.89 ± 1.67 vs. 0.30 ± 0.95 ml/min/1.73 m² per month, p = 0.002). Significantly higher rates of decline in creatinine clearance were noted in patients with TNF-α (rs1800629) GA+AA than GG genotype (0.88 ± 1.83 vs. 0.36 ± 0.70, p = 0.03), and with IL-10 (rs1800896) AG+GG than AA genotype (1.28 ± 2.14 vs. 0.33 ± 0.90, p < 0.001). Conclusions: Gene polymorphisms of IL-10 and TNF-α are associated with CIN risk and long-term renal outcome after PCI. More prospective studies are needed to confirm our results.

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF −308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF −308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-α is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a significant increased plasma fibrinogen levels. Similar and probably additive effects on might have a genetically determined increased production of pro-thrombin even if no significant differences in genotype frequencies of pro-thrombin (FII) 20210G/A polymorphisms were observed in this study. All together these results, indicating the relationship among genetically determined TNFα and FII production and increased levels of tissue damage markers of AMI, suggest that a complex genetic background, might be involved in susceptibility to AMI in young men influencing the extension and severity of the disease.

Association of TNF-α gene polymorphisms with Graves disease susceptibility and early course thyroid stimulating hormone receptor antibody level in Chinese Han population in Anhui region

To assess the association of tumour necrosis factor-α (TNF-α) gene polymorphisms at positions -863C/A, -857C/T, -238G/A and Graves disease (GD) susceptibility in Chinese Han population in Anhui region. The polymorphisms of TNF-α gene were determined by polymerase chain reaction with specific primers in 254 patients affected with GD and 212 healthy controls. Allelic and genotypic frequencies in GD group and normal controls as well as in different genders were compared. The allelic and genotypic frequencies for different thyroid stimulating hormone receptor antibody (TRAb) levels (TRAb > 12 U/L; ≤12 U/L) were also compared among patients with earlier onset GD. (1) The A allele at -863C/A locus in GD group (16.73%) was significantly greater than that of the control group (11.79%) (P< 0.05, OR = 1.503); the frequency of AA+CA genotype of -863C/A locus in GD group (32.68%) was significantly greater than that of control group (23.58%) (P< 0.05, OR = 1.573). There was no significant difference (P> 0.05) in the allelic and genotypic frequencies of -857C/T, -238G/A loci between the two groups. (2) There was no significant difference (P> 0.05) in the allelic and genotypic frequencies of -863C/A, -857C/T, -238G/A loci between patients of different genders. (3) There was no significant difference (P>0.05) in such frequencies between patients with earlier onset GD and different TRAb levels (TRAb > 12 U/L; ≤12 U/L). (1) The -863 A allele of TNF-α gene may contribute to the development of GD in Chinese Han population in Anhui, whilst -857C/T, -238G/A alleles may not. (2) There is no association between TNF-α gene -863C/A, -857C/T, -238G/A polymorphisms and development of GD in different genders. (3) There was no association between above polymorphisms and TRAb levels in patients with earlier onset GD.

Pharmacogenetic Analysis of TNF, TNFRSF1A, and TNFRSF1B Gene Polymorphisms and Prediction of Response to Anti-TNF Therapy in Psoriasis Patients in the Greek Population

Although biologic therapies have revolutionized the treatment of psoriasis, patients exhibit a substantial heterogeneous response that could be due to complex genetic heterogeneity. The aim of this study was to investigate the possible influence of tumor necrosis factor-α (TNF), TNF receptor I (TNFRSF1A), and TNF receptor II (TNFRSF1B) gene polymorphisms on anti-TNF treatment responsiveness in psoriasis patients. A Greek multicenter collaboration was established to recruit a cohort of patients (n = 80) with psoriasis treated with anti-TNF drugs. Single nucleotide polymorphisms (SNPs) in TNF (-238G>A, -308G>A, -857C>T), TNFRSF1A (36A>G), and TNFRSF1B (676T>G) were genotyped by PCR-restriction fragment length polymorphism assays. SNPs and haplotypes, including stratification by comorbidity status, were analyzed for association with treatment response after 6 months of therapy, defined as a reduction in the Psoriasis Area and Severity Index (PASI) score by >75% (responders) or ≤50% (nonresponders). Sixty-three patients (78.8%) were defined as responders (PASI score reduction >75%) and 17 patients (21.2%) were defined as nonresponders (PASI score reduction ≤50%). Carriage of TNF -857C or TNFRSF1B 676T alleles was associated with positive response to drug treatment in patients treated with etanercept (p = 0.002 and p = 0.001, respectively). None of the genotyped SNPs were associated with responsiveness to treatment with infliximab or adalimumab. Additionally, when patients were stratified by comorbidity status, none of the genotyped SNPs were alone associated with responsiveness to drug treatment. This study is the first in the field of psoriasis demonstrating a strong association between genetic markers and positive response to drug treatment. Validation of this result in larger studies, as well as analysis of other drug treatments, could provide the basis for individually tailored treatment, along with increased cost effectiveness and reduced unnecessary exposure to toxicity.

Interaction between tumour necrosis factor-α gene polymorphisms and substance use on risk of betel quid-related oral and pharyngeal squamous cell carcinoma in Taiwan

ObjectiveBetel quid (BQ) components induce the secretion of tumour necrosis factor-alpha (TNF-α) in oral keratinocytes, which promotes oral mucosal inflammation and oral cancer. This study was carried out to evaluate the association of TNFA genetic variants (−308G>A and −238G>A) with the risk and prognosis of BQ-related oral and pharyngeal squamous cell carcinoma (OPSCC). DesignA total of 403 subjects (205 cancer cases and 198 healthy controls) who habitually chewed BQ were recruited. The genotypes were determined by TaqMan real-time assays. ResultsG allele and G/G genotype at TNFA −308 were associated with a 1.95-fold (95%CI: 1.16–3.28, pcorrected=0.024) and 2.28-fold (95%CI: 1.30–4.00, pcorrected=0.008) increased risk of cancer as compared to those with A allele or A/A+A/G genotypes, respectively. In addition, G allele (p=0.080) and G/G genotype (p=0.076) at TNFA −238 were associated with a borderline but statistically significant increased risk of OPSCC. The combined G/G+G/G genotype at both loci had a 2.37-fold increased risk of OPSCC as compared to those with other combined genotypes (95%CI: 1.41–4.00, p=0.001). Interactions between combined genotypes and smoking status were also found to contribute to risk of BQ-related OPSCC. There was no association of TNFA genotypes with clinicopathologic findings or the survival of OPSCC patients. ConclusionsBQ-chewers who carry the G allele or G/G genotype in TNFA −308 may have an increased risk of OPSCC. The intensity of cigarette smoking modulates the effect of the combined TNFA genotypes on risk of BQ-related OPSCC.

ACTN3 and TNF gene polymorphism association with C-reactive protein, uric acid, lactate and physical characteristics in young African cricket players.

The genotyping of α-actinin-3 (ACTN3) and tumor necrosis factor-α (TNF) genes of 31 Zulu South African males aged 20 to 27 years (14 cricketers and 17 controls) was performed by PCR amplification followed by restriction digestion. After ANOVA the associations with C-reactive protein (CRP), uric acid (UA), lactate (LA) and physical characteristics were examined using Chi2maximum likelihood test and Fisher’s exact test. ACTN3 genotype frequencies for the cohort were 90.3% RR and 9.7% RX. The XX genotype was absent. R allele at high frequency of 100% was associated with CRP <3.0 mg/L in cricketers (p=0.0001) and controls (p=0.0140). High R allele frequencies of 80 to 100% were associated in cricketers with lower uric acid (p=0.0001), lactate (p=0.0003) and with body mass index (BMI) and Fat mass (FM) (p=0.0001). TNF genotyping displayed 42% GG, 45% GA and 13% AA for the cohort. CRP <3.0 mg/L was associated (p=0.0001) with A allele frequency (40% cricketers and 18% controls). Associations (p=0.0001) of A allele frequency (9 to 22%) with BMI, Lean body mass (LBM) and FM were found. The genotyping of cricketers was done for the first time.The study demonstrates a strong ACTN3 R allele association with lower CRP, UA and LA levels. The findings of XX null genotype and TNF 308A allele association with CRP inflammatory marker provide evidence about the genotype distribution of previously unexamined homogeneous cohort of African athletes. Key words: Tumor necrosis factor-α (TNF) genotype, α-actinin-3 (ACTN3) genotype, polymorphism, C-reactive protein, physical characteristics, Zulu South African cricket players

Association of Interferon-γ, Interleukin-10, and Tumor Necrosis Factor-α Gene Polymorphisms with Occurrence and Severity of Eales' Disease

Eales' disease (ED) is an idiopathic retinal vasculitis characterized by capillary nonperfusion and neovascularization. Previous reports on ED demonstrated that T-cell-mediated immunoresponse and differential cytokine production in inflammatory and angiogenic stage seem to influence the extent and severity of this disease. Therefore, the purpose of this study is to investigate the influence of cytokine gene polymorphisms on occurrence and severity of ED. One hundred twenty-one patients with ED were recruited from an Eastern Indian population and compared with 223 matched healthy control subjects. Genotyping of IFN-γ, IL-10, and TNF-α were performed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). A statistically significant association was found between the IL-10 -1082AA (P = 0.002), TNF-α -308AA (P = 0.0017) genotypes and the IL-10 ATA haplotype (P = 0.0123) and the occurrence of ED. In addition IL-10 -1082GG (P = 0.0005), TNF-α -308GG (P < 0.0001) genotype were found to be protective against disease occurrence. A synergistically low IL-10/high TNF-α genotype increased the risk of development (P < 0.0001) and the severity (P = 0.019) of ED. These data suggest that a low IL-10-expressing and high TNF-α-expressing genotype of the host can influence the occurrence and severity of outcome of ED.

Association between Tumor Necrosis Factor-α Gene Polymorphism and Bronchopulmonary Dysplasia in Preterm Infants

Association between Tumor Necrosis Factor-α Gene Polymorphism and Bronchopulmonary Dysplasia in Preterm Infants

Tumor Necrosis Factor-α Gene Polymorphisms in Korean Children with Inflammatory Bowel Disease

Purpose: The aim of this study was to investigate the existence of TNF-α polymorphisms in Korean children with Crohn’s disease (CD), ulcerative colitis (UC), as compared to healthy controls. Methods: Blood samples were obtained from 40 patients with CD, 14 patients with UC, and 30 healthy controls. Genotyping for 5 TNF-α polymorphisms (G238A, G308A, C857T, C863A, and T1031C) was performed. The allele frequencies for the inflammatory bowel diseases, CD and UC, were measured in patients with these disease and in healthy controls, and these allele frequencies were compared between the 3 groups. We examined the significant association between polymorphism and disease phenotype, such as location, behavior, perianal disease, and pediatric Crohn’s activity index (PCDAI) in CD. Results: Based on our findings, the TNF-α allele frequencies of G238A, G308A, C857T, C863A, and T1031C were 3.3, 8.3, 16.7, 16.7, 21.7% in healthy control, 2.5%, 7.5%, 18.8%, 20.0%, 22.5% in CD, 7.1%, 7.1%, 7.1%, 21.4%, 28.6% in UC. They were no statistically significant differences between the 3 groups. There were no associations between genotypes and phenotypes in CD, except a statistically significant higher allele frequency of G238A in ileal type (L1) disease (p=0.010). Conclusion: Our results indicate that 5 TNF-α polymorphisms do not seem to be associated with susceptibility to inflammatory bowel disease in Korean pediatric patients even though young patients were anticipated to have a stronger genetic affiliation for these diseases than adult patients. We think that further studies are needed to find those genes associated with susceptibility to CD and UC in Korean pediatric patients with inflammatory bowel disease. (Korean J Pediatr Gastroenterol Nutr 2011; 14: 269∼278)

Potential role of Neuregulin 1 and TNF-alpha (−308) polymorphism in schizophrenia patients visiting hospitals in Lahore, Pakistan

Schizophrenia is a chronic and disabling disease of the brain. Schizophrenic patients have auditory hallucinations, delusions and reduced social skills. Recent studies suggest that the genetic polymorphisms are linked with development of schizophrenia. Polymorphisms of schizophrenia susceptibility and different cytokine genes act as the genetic markers. The objective of our study is to examine the association between the neuregulin 1 and tumor necrosis factor-α (-308) gene polymorphism with schizophrenia. This association was performed on the basis of molecular biology to screen the mutations of neuregulin 1 and tumor necrosis factor-α (-308) gene in schizophrenic patients by polymorphism analysis. Statistical analysis of the observed data shows that there was an association (P = 0.003) between patient's group and controls in terms of genotypes of single-nucleotide polymorphism 1 rather than single-nucleotide polymorphism 2 of neuregulin 1. So, heterozygous (adenine/guanine) allelic pattern can be a higher risk factor of schizophrenic patients. Polymorphism of tumor necrosis factor-α (-308) gene indicated frequent presence of homozygous (adenine/adenine) allelic pattern in patient's group than in controls (P = 0.015). Statistical analysis indicates that the age distribution has significant difference between patient's group and controls (P = 0.022) while the gender ratio is not significantly different (P = 0.366) between the two groups. It was concluded that in Pakistani population the neuregulin 1 and tumor necrosis factor-α (-308) genes are strongly associated with schizophrenia.

TUMOR NECROSIS FACTOR-α GENE POLYMORPHISMS IN AGE-RELATED MACULAR DEGENERATION

The purpose of this study was to investigate tumor necrosis factor-α gene polymorphisms in unrelated Taiwan Chinese patients with wet age-related macular degeneration (AMD) and controls. In this retrospective case-control study, we enrolled 190 wet AMD patients and 180 age- and gender-matched controls. Genomic DNA was extracted from the peripheral blood obtained from wet AMD patients and control subjects. Polymerase chain reaction was performed to analyze 6 candidate single nucleotide polymorphisms in the tumor necrosis factor-α gene: -238 G/A, -308 G/A, +489 G/A, -857 C/T, -863 C/A, and -1031 T/C. Among the 6 candidate single nucleotide polymorphisms of the tumor necrosis factor-α gene, only -1031 T/C was significantly associated with wet AMD. The distribution of the -1031 T/C genotypes was significantly different between wet AMD patients (homozygous T [TT], 64%; TC heterozygous [TC], 36%; homozygous C [CC] 0%) and controls (TT, 66%; TC, 28%; CC, 7%; P = 7 × 10⁻⁴). The genotype CC of -1031 T/C was significantly lower than that in controls (0 vs. 7%, P = 1.45 × 10⁻⁴, odds ratio = 14.70, 95% confidence interval = 1.90-33.59). No single haplotype was found to be significantly associated with either wet AMD patients or controls. Our data indicate that the tumor necrosis factor-α -1031 T/C polymorphism may be associated with wet AMD in the Taiwan Chinese population.

Tumour necrosis factor-α promoter region polymorphisms affect the course of spontaneous HBsAg clearance

This study aimed to investigate the roles of tumour necrosis factor-α (TNF-α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection. Polymorphisms in the TNF-α (-1031 T to C, -863 C to A, -857 C to T, -308 G to A and -238 G to A transition) gene were evaluated in 274 chronic HBV-infected patients and 194 patients with resolved HBV infection. The peripheral blood mononuclear cells (PBMC) isolated from 77 (28%) of the 274 chronic HBV-infected patients with negative HBeAg and positive antibody to HBeAg were stimulated with HBcAg. Data on TNF-α genotypes and phenotypes in subjects with/without the A allele at the TNF-α-863 promoter single nucleotide polymorphism (rs1800630) were compared. The A allele in the -863 promoter region of the TNF-α gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; P<0.01). The TNF-α-863 A allele genotype predicted lower TNF-α production by PBMC after in vitro HBcAg stimulation (P<0.02). The A allele at the -863 locus of the promoter region of the TNF-α gene predicts lower HBcAg-inducible TNF-α secretion. It is also associated with chronicity of HBV infection.

Tumour necrosis factor-α gene polymorphisms in asbestos-induced diseases

Background: Tumour necrosis factor (TNF)-α influences the pathogenesis of lung fibrosis and carcinogenesis in normal cells. Polymorphisms of this gene have been suggested to be associated with susceptibility to lung diseases.Methods: Association studies were performed in German subjects, using control subjects (n = 177), pulmonary fibrosis patients (n = 612) and bronchial carcinoma patients (n = 374).Results: Compared with a healthy (control) group, a significant result could be obtained for the asbestosis (patient) group (crude odds ratio (ORcrude) = 1.57; 95% confidence interval (CI) 1.05–2.36; p = 0.03), especially with severe lung asbestosis (ORcrude = 4.15; 95% CI 1.06–16.16; p = 0.04). A significant association was revealed when comparing asbestosis patients (ORcrude = 4.08; 95% CI 1.53–10.54; p = 0.004 and ORadjusted = 3.89; 95% CI 1.49–10.17; p = 0.006) with asbestos-induced lung cancer patients.Conclusion: The results confirm the hypothesis that TNF-α polymorphisms are associated with asbestos-induced fibrotic or malignant lung diseases in Germans.

G protein β3 subunit, interleukin-10, and tumor necrosis factor-α gene polymorphisms in Koreans with irritable bowel syndrome

The association between irritable bowel syndrome (IBS) based on Rome III criteria and G protein beta3 subunit (GNB3), interleukin (IL)-10, and tumor necrosis factor (TNF)-alpha gene polymorphisms is uncertain. Case and control subjects were recruited from Korean visitors to the Health Promotion Center and Digestive Disease Center for gastrointestinal endoscopy. G protein beta3 subunit, IL-10, and TNF-alpha gene polymorphisms were genotyped using a polymerase chain reaction-based method. Multifactor dimensionality reduction (MDR) analysis was used to assess gene-gene interactions. Genotype and allele frequencies of GNB3 showed marginal significance between the healthy controls and IBS patients (chi(2) = 5.92, P = 0.052; chi(2) = 3.76, P = 0.053). G protein beta3 subunit T allele was more strongly correlated with IBS with constipation (12 of constipation-dominant type and 31 of mixed type) than with 51 diarrhea-dominant type and 88 normal subjects (chi(2) = 13.91, P = 0.008). Multifactor dimensionality reduction analysis revealed that there were no significant interactions of GNB3, IL-10, and TNF-alpha gene variants with susceptibility to IBS (P > 0.05). The results suggest that GNB3 825T allele might be associated with IBS with constipation in Koreans.

Tumor Necrosis Factor-α Gene Polymorphisms Are Associated with Severity of Acute Graft-Versus-Host Disease Following Matched Unrelated Donor Bone Marrow Transplantation in Children: A Pediatric Blood and Marrow Transplant Consortium Study

Tumor necrosis factor (TNF)-alpha plays a significant role in conditioning related toxicities and the development of acute graft-versus-host disease (aGVHD). TNF-alpha gene polymorphisms are associated with rejection after organ transplantation and aGVHD in matched related donor blood and marrow transplantation (BMT) recipients. Few studies have been published on unrelated donor BMT in the pediatric age group. In this study, we examined the relationship between specific polymorphisms in TNF pathway genes and the occurrence and severity of aGVHD. Recipient single-nucleotide polymorphisms (SNPs) in TNF-alpha and TNF receptor superfamily members 1A (TNFRSF1A) and 1B (TNFRSF1B) were investigated. In a multi-institutional Pediatric Blood and Marrow Transplant Consortium trial, a total of 180 pediatric patients (mean age, 11.0 years) were prospectively evaluated for clinical outcomes after matched unrelated donor BMT. All patients received myeloablative conditioning and two-drug GVHD prophylaxis with cyclosporine or tacrolimus, with methotrexate in the majority of patients. TNF-alpha genotypes were not correlated with the overall incidence of aGVHD. Significant associations were seen between TNF-alpha variant alleles and the severity of aGVHD (grade II-IV and grade III-IV), especially when analyzed in whites only (n = 165). Grade II-IV aGVHD was correlated with recipient -857T allele (hazard ratio [HR], 0.47; P = .04), -238A allele (HR, 1.76; P = .002), and d3/d3 genotype (HR, 0.64; P = .03). Severe (grade III-IV) aGVHD was associated with TNF-alpha -1031C allele (HR, 2.38; P = .03), -863A allele (HR, 3.18; P = .003), and d4/d4 genotype (HR, 2.82; P = .01). After adjusting for clinical factors, the association of -1031C, -863A, -238A, and d4/d4 genotypes with severity of aGVHD remained statistically significant. No correlation between selected SNPs in TNFRSF1A or TNFRSF1B and the incidence or severity of aGVHD was found. Our findings indicate clinically important relationships between genetic polymorphisms in TNF-alpha and the severity of aGVHD in this cohort. Improved understanding of this relationship may allow for a risk-adjusted approach to GVHD prevention in pediatric BMT.

Tumor Necrosis Factor Polymorphisms and Alcoholic Liver Disease: A HuGE Review and Meta-Analysis

The association between alcoholic liver disease (ALD) and tumor necrosis factor-alpha gene (TNFA) polymorphisms has been analyzed in several studies, but results have been conflicting. The main purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility to ALD. The authors surveyed studies on the relation between TNFA gene polymorphisms and ALD by means of an electronic database search. A meta-analysis was conducted in a random-effects model. The association between ALD and the -238G>A or -308G>A polymorphism of the TNFA gene has been analyzed in 11 studies. Concerning the -238G>A polymorphism, the authors found a significant association between possession of the A allele and risk of alcoholic liver cirrhosis (odds ratio = 1.47, 95% confidence interval: 1.05, 2.07). Meta-analysis of the relation between the -308G>A polymorphism and ALD did not show any significant association. Given the limited number of studies and the potential biases, more data are needed to confirm the association described for the -238A allele.

Interleukin-1 and tumor necrosis factor-α gene polymorphisms in Turkish patients with localized aggressive periodontitis

Localized aggressive periodontitis (LAgP) is a complex multifactorial periodontal disease to which genetic factors are thought to predispose individuals. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are potent immunomodulators and proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune and infectious diseases and proposed to be risk factors for LAgP. Our aim was to investigate IL-1 alpha (+4845), IL-1 beta (+3954), and TNF-alpha (-308) gene polymorphisms in Turkish LAgP patients. We genotyped 31 LAgP patients and 31 healthy controls for IL-1alpha(+4845), IL-1beta(+3954), and TNF-alpha(-308) using standard PCR amplification followed by restriction enzyme digestion and gel electrophoresis. Higher prevalence of heterozygosity for IL-1alpha(+4845) was found in cases (65%) when compared to controls (35%) (P < 0.05). While homozygous allele 1 of IL-1beta(+3954) was the most frequent genotype in cases (62%), no controls were homozygous for this allele (P < 0.001). Homozygous allele 1 was the most common TNF-alpha genotype in both groups, however no significant difference in TNF-alpha genotypes was found between groups. In conclusion, in this Turkish population, susceptibility to LAgP is increased by heterozygosity for allele 1 of IL-1alpha(+4845) or homozygosity for allele 1 of IL-1beta(R+3954). Moreover, IL-1 gene polymorphisms appear to have a role in susceptibility to LAgP, and the above-mentioned genotypes could be an important risk factor for LAgP in the Turkish population.