The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case-control study.
ABSTRACT: BACKGROUND: The aim of this study was to investigate the role of TNF genetic variants and the combined effect between TNF gene and cigarette smoking in the development of gastric cancer in the Korean population. METHODS: We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the TNF gene, TNF-alpha-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C, and TNF-beta 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the TNF gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential TNF gene-gene interactions. RESULTS: TNF-alpha-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0-2.5 for CT genotype; OR = 2.6, 95% CI 1.0-6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of TNF-alpha-1031 T/C, TNF-alpha-863 C/A, and TNF-alpha-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, TNF-alpha-857 C/T was included in the first list of SNPs with a significant main effect. CONCLUSION: TNF-alpha-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by TNF genetic effect is pronounced by cigarette smoking.
Project description:The aim of the present study was to evaluate the relationship between tumor necrosis factor-? (TNF-?) and the development of gastric cancer, and to investigate whether it can be used as a biological marker for gastric cancer. In the current study, a new meta-analysis was performed to assess the association between TNF-? gene polymorphisms and gastric cancer susceptibility. Subgroup analyses based on ethnicity, control population source and non-cardia cancers were also conducted. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. TNF-? 308 polymorphisms indicated a significant relationship with gastric cancer risk among a normal population [GA/AA vs. GG; 1.17 (1.10-1.23)]. In analysis stratified by ethnicity, TNF-? 238 displayed an association with gastric cancer risk in eastern populations [GA/AA vs. GG: 1.24 (1.02-1.50)], but not in western populations [GA/AA vs. GG: 0.96 (0.79-1.18)]. The overall ORs (95% CIs) for TNF-? 857, TNF-? 1031 and TNF-? 863 were 1.13 (1.04-1.24), 0.94 (0.85-1.05) and 0.89 (0.78-1.02), respectively, under dominant genetic model comparison. Among the above three SNPs, only TNF-? 857 was robustly associated with gastric cancer inclination, and this association remained consistently robust when limited to non-cardia gastric cancers [GA/AA vs. GG: 1.16 (1.03-1.31)]. TNF-? 308 and TNF-? 857 genotypes were potential risk factors of statistical significance in gastric cancer, and TNF-? 238 indicated to be significantly associated with gastric cancer risk only in eastern populations. TNF-? 1031 and TNF-? 863 were not significantly associated with gastric cancer risk.
Project description:Functional polymorphisms of tumor necrosis factor-alpha (TNF-?) may play a critical role in the regulation of immune and inflammatory responses and could affect transcriptional levels of the TNF-? gene and thus contribute to carcinogenesis and outcomes of cancer patients. In a cohort study, we explored the associations between TNF-? polymorphisms and risk of recurrence of squamous cell carcinoma of the nonoropharynx (SCCNOP). We used log-rank test and multivariable Cox models to evaluate the associations between TNF-? polymorphisms and risk of recurrence. In overall comparisons, patients with the TNF-? -857 CC, TNF-? -863 CC and TNF-? -1031 TT genotypes had significantly worse disease-free survival (log-rank, p = 0.014, log-rank, p = .020, and log-rank, p = .002, respectively) and higher risk of disease recurrence than patients with the corresponding variant genotypes, respectively (hazard ratio [HR], 1.4, 95% CI, 1.1-1.9, HR, 1.4, 95% CI, 1.0-1.8 and HR, 1.6, 95% CI, 1.2-2.2, respectively). However, no significant association was detected for the TNF-? -308 polymorphism. Moreover, in further stratified analyses based on smoking status and treatment, we found that the associations of the TNF-? -857, TNF-? -863 and TNF-? -1031 polymorphisms with risk of recurrence were more pronounced in smokers and patients treated with chemoradiation. Our findings support a significant role of the TNF-? -857, TNF-? -863 and TNF-? -1031 polymorphisms in recurrence of SCCNOP, especially in smokers and patients treated with chemoradiation. Future prospective studies with larger sample size are needed to confirm these findings.
Project description:To investigate associations between the tumor necrosis factor alpha (TNF-?) -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A polymorphisms and HCC in Korea.Hepatocellular carcinoma (HCC) cases were diagnosed at CHA Bundang Medical Center from June 1996 to August 2008. The association between TNF-? polymorphisms and HCC was analyzed in 157 HCC patients and 201 controls using a polymerase chain reaction-restriction fragment length polymorphism assay. We investigated five TNF-? polymorphisms, which are TNF-? -1031 T>C, -863 C>A, -857 C>T, -308 G>A, and -238 G>A. The TNF-? genotype frequencies, genotype combinations and haplotypes were analyzed to disclose the association with HCC.None of the TNF-? polymorphisms was significantly associated with HCC. However, nine genotype combinations had associations with increased likelihood of HCC. Among them, TNF-? -1031/-857/-238 TT/CC/GA (AOR = 18.849, 95%CI: 2.203-161.246, P = 0.007), TNF-? -1031/-308/-238 TT/GG/GA (AOR = 26.956, 95%CI: 3.071-236.584, P = 0.003), and TNF-? -1031/-238 TT/GA (AOR = 21.576, 95%CI: 2.581-180.394, P = 0.005) showed marked association with HCC. There were five haplotypes of TNF-? polymorphisms which were significantly associated with HCC. They are TNF-? -1031/-863/-857/-308/-238 T-C-C-G-A (OR = 25.824, 95%CI: 1.491-447.223, P = 0.0005), TNF-? -1031/-857/-308/-238 T-C-G-A (OR = 12.059, 95%CI: 2.747-52.950, P < 0.0001), TNF-? -1031/-857/-238 T-C-A (OR = 10.696, 95%CI: 2.428-47.110, P = 0.0001), TNF-? -1031/-308/-238 T-G-A (OR = 7.556, 95%CI: 2.173-26.280, P = 0.0002) and TNF-? -1031/-238 T-A (OR = 10.865, 95%CI: 2.473-47.740, P = 0.0001). Moreover, HCC Okuda stage III cases with the TNF-? -1031 CC genotype had better survival than those with the TT genotype (AOR = 5.795, 95%CI: 1.145-29.323).Although no single TNF-? polymorphism is associated with HCC in this study, some TNF-? genotype combinations and haplotypes are associated with HCC. In addition, HCC Okuda stage III cases with the TNF-? -1031 TT genotype may have a better prognosis than those with the CC genotype.
Project description:Although the etiology of Behçet's Disease (BD; MIM 109650) remains to be clearly elucidated, levels of tumor necrosis factor alpha (TNF-alpha) have been reported to be significantly elevated in BD patients, and TNF-alpha blockers have been demonstrated to exhibit some degree of therapeutic efficacy for a certain subset of BD sufferers. In this study, we have conducted an analysis of the TNFA haplotypes in the promoter response element that affect the binding affinity of specific transcription factors, in order to characterize their association with the clinical features of BD. Six polymorphisms in the promoter region of TNFA were genotyped in 254 BD patients and 344 control subjects, via the PCR-RFLP technique. TNFA -1031*C, -863*A and -308*G alleles were associated with an increased risk of BD (p=0.030, OR=1.4; p=0.008, OR=1.5; p=0.010, OR=1.8, respectively). The sole TNFA haplotype -1031C-863A-857C-376G-308G-238G, was associated with a 1.6 fold increase in the risk of BD, whereas the TNFA haplotype -1031T-863C-857C-376G-308A-238G was associated with a 0.6 decreased risk of BD. The TNFA -1031*C, -863*A, -857*C and -308*G alleles were significantly associated with BD. The findings of this study, collectively, indicate that TNFA haplotypes in the promoter response elements may exert significant influence on susceptibility to BD.
Project description:The promoter variants of TNF-?, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF-? promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF-? polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log-rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF-? -308 and TNF-? -863 polymorphisms, patients with common homozygous genotypes had worse disease-free survival (log-rank p = 0.0002 and p < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3-2.8 and HR, 1.9, 95% CI, 1.3-2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-? -308 and -863 polymorphisms had worse disease-free survival (log-rank p = 0.005 and p = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4-18.4 and HR, 3.7, 95% CI, 1.5-9.1, respectively), while no such significant associations were found for TNF-? -857 or -1031 polymorphisms. Our findings suggest that TNF-? -308 and -863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors. However, larger studies are needed to validate these results.
Project description:AIM:To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-alpha and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS:Ten variants in GR, TNF-alpha and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS:For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-alpha gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-alpha, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively. CONCLUSION:This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.
Project description:BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology, in which genetic factors, seem to play an important role in the disease predisposition and course. Assessment of tumor necrosis factor (TNF-?) gene polymorphisms in many populations showed a possible association with IBD. Considering the genetic variety in different ethnic groups, the aim of the present study was to investigate the association of five important single nucleo-tide polymorphisms (SNPs) in the promoter region of (TNF-?) gene with IBD in Iran. METHODS: In this case-control study, 156 Ulcerative colitis (UC) patients, 50 Crohn's disease (CD) patients and 200 sex and age matched healthy controls of Iranian origin were enrolled. The study was performed during a two year period (2008-2010) at Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. DNA samples were evaluated for (TNF-?) gene polymorphisms (including -1031, -863, -857, -308 and -238) by PCR and RFLP methods. RESULTS: The frequency of the mutant allele of -1031 polymorphism was significantly higher in Iranian patients with Crohn's disease compared to healthy controls (P=0.01, OR=1.92; 95% CI: 1.14-3.23). None of the other evaluated polymorphisms demonstrated a significant higher frequency of mutant alleles in Iranian IBD patients compared to controls. CONCLUSION: Among the five assessed (SNPs), only -1031 polymorphism of (TNF-?) gene may play a role in disease susceptibility for Crohn's disease in Iran. This pattern of distribution of (TNF-?) gene polymorphisms could be specific in this population.
Project description:Since apoptosis and survival of the immune cells are crucially important in prevention or predisposition of individual from/to infections, especially in intracellular ones, the current study was performed to assess the correlation of host genetic polymorphisms with susceptibility to TB. For this reason, we investigated the difference of the single nucleotide polymorphisms [SNPs] in tumor necrosis factors [TNF-α] genes at (-238, -308, -857 and -863 position) and tumor necrosis factors receptors two [TNFR2] at (T 587 G position) between patients [n=151] and control [n=83]. The genotyping was studied by using PCR-RFLP which had high sensitivity in detecting compared with other techniques. The results showed a strong correlation between two polymorphisms in different loci of TNF-α gene including TNF-α T-857 C and A 238 G. But no association were found in TNFR2 genes with susceptibility to TB. And we found no correlation between TNFR2 and TNF-α gene polymorphisms. Therefore, the TNF-α T 857 C and A 238 G SNPs could be promising marker for identifying risk populations.
Project description:BACKGROUND: The development of osteoarthritis (OA) involves inflammation, but the evidence for participation of genes propagating or inhibiting inflammation in the OA process is inconsistent. We investigated the associations of common variants in the TNF? gene, and their interactions with other cytokine genes, with hand OA among Finnish women. METHODS: This cross-sectional study was based on bilateral hand radiographs of 542 female dentists and teachers which were classified according to the presence of OA (radiographic K-L score ? 2 in ? 3 joints) using reference images. The genotypes were determined by PCR-based methods. The degree of pairwise linkage disequilibrium (LD) and haplotypes were constructed and analyzed by the SNPStats software. The associations between four TNF? SNPs and hand OA were tested using logistic regression adjusting for age, occupation, and BMI, and fitting a log-additive model of inheritance. Gene-gene interactions of TNF? SNPs with IL4R and IL10 SNPs were examined by stratified logistic regression analyses. Possible interactions of the TNF? SNPs with variants in the previously reported IL1? and IL6 genes in influencing hand OA were also explored. RESULTS: Two TNF? polymorphisms ("-1031" and "-863") were associated with hand OA (OR = 1.45, 95% CI 1.01-2.07 and 1.55, 1.06-2.25, respectively). These associations retained when adjusting further for IL1? "3954" and IL6 "174". The TNF? G-A-G haplotype was associated with an increased risk of hand OA (1.61, 1.10-2.37, p = 0.01). Interactions were observed between TNF? "-1031" and IL4R Ser503Pro, TNF? "-1031" and IL10 "-1082", and TNF? "-863" and IL10 "-1082" SNPs with regard to hand OA (p = 0.012, p = 0.0068, and p = 0.02, respectively). The carriage of the TNF? "-1031" minor allele doubled the risk (2.01, 1.26 - 3.22) only in women with the IL4R Ser/Ser genotype. Similarly, the TNF? "-1031" and "-863" minor alleles were associated with an increased risk of hand OA only in IL10 G/G or A/A homozygotes (2.54, 1.45-4.47 and 2.60, 1.46-4.62, respectively) but not in heterozygotes (G/A). CONCLUSIONS: Our results suggest that the TNF? gene variants play a role in the etiology of hand OA. In addition, the findings are suggestive of a gene-gene interaction of the TNF? with IL4R and IL10 genes.
Project description:Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF-?) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS.We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 h) and MODS. MODS was defined as failure of ?2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 h. Subjects were genotyped by DNA sequencing and analyzed for SNPs at -1031 C/T (rs1799964), -863 A/C (rs1800630), -857 C/T (rs1799724), -308 A/G (rs1800629), and -238 A/G (rs361525).Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at -1031C (56.5% vs. 32.4% P = 0.022, OR: 2.7; 95%CI: 1.12-6.51) and -863A (43.5% vs. 21.8% P = 0.022, OR: 2.76; 95%CI: 1.12-6.74).TNFA promoter variants do not alter susceptibility to AP, but rather the TNF-? expression-enhancing -1031C and -863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF-? in the overall AP syndrome.