Association of TNFA promoter region haplotype in Behcet's Disease.
ABSTRACT: 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:Tumor necrosis factor-alpha (TNF-alpha) is a potent catabolic factor to skeletal muscle. Single-nucleotide polymorphisms (SNPs) in the promoter region of the TNF-alpha coding gene, TNF, have been implicated in the interindividual variation in TNF-alpha production via transcriptional regulation. The present study investigated the association of muscle phenotypes with five TNF promoter SNPs, which potentially have biological significance. Female and male volunteers (n = 1,050) from the Baltimore Longitudinal Study of Aging were genotyped, and their regional and total body muscle mass, and arm and leg muscle strength were measured. Results indicated that putative high-expression alleles at positions -1031 and -863, individually or in combination in the haplotype 1031C-863A-857C-308G-238G, were associated with lower muscle mass in men. Specifically, carriers of -1031C, compared with noncarriers, exhibited lower arm muscle mass (6.4 +/- 0.1 vs. 6.8 +/- 0.1 kg, P = 0.01) and appendicular skeletal muscle mass (ASM) (24.3 +/- 0.4 vs. 25.4 +/- 0.2 kg, P = 0.02), with leg muscle mass and the ASM index (ASMI; kg/m(2)) also tending to be lower (P = 0.06 and 0.07). Similarly, -863A allele carriers (linked with -1031), compared with noncarriers, exhibited lower arm muscle mass (6.4 +/- 0.1 vs. 6.8 +/- 0.1 kg, P = 0.04). Carriers of the haplotype 1031C-863A-857C-308G-238G, compared with noncarriers, exhibited lower arm muscle mass (6.3 +/- 0.2 vs. 6.8 +/- 0.1 kg, P < 0.01), trunk muscle mass (25.7 +/- 0.5 vs. 26.9 +/- 0.3 kg, P < 0.05), and ASM (24.1 +/- 0.5 vs. 25.3 +/- 0.2 kg, P < 0.025), with tendencies for lower leg muscle mass and ASMI (P = 0.07 and 0.08). Results indicate that genetic variation in the TNF locus may contribute to the interindividual variation in muscle phenotypes in men.
Project description:TNF-? and IFN-? play a role in the development of mucosal damage in celiac disease (CD). Polymorphisms of TNFA and IFNG genes, as well as of the TNFRSF1A gene, encoding the TNF-? receptor 1, might underlie different inter-individual disease susceptibility over a common HLA risk background. The aims of this study were to ascertain whether five SNPs in the TNFA promoter (-1031T>C,-857C>T,-376G>A,-308G>A,-238G>A), sequence variants of the TNFRSF1A gene and IFNG +874A>T polymorphism are associated with CD in a HLA independent manner.511 children (244 CD, 267 controls) were genotyped for HLA, TNFA and INFG (Real Time PCR). TNFRSF1A variants were studied (DHPLC and sequence).Only the rare TNFA-1031C (OR=0.65, 95% CI:0.44-0.95), -857T (OR=0.42, 95% CI:0.27-0.65), -376A (OR=2.25, 95% CI:1.12-4.51) and -308A (OR=4.76, 95% CI:3.12-7.26) alleles were significantly associated with CD. One TNFRSF1A variant was identified (c.625+10A>G, rs1800693), but not associated with CD. The CD-correlated TNFA SNPs resulted in six haplotypes. Two haplotypes were control-associated (CCGG and TTGG) and three were CD-associated (CCAG, TCGA and CCGA). The seventeen inferred haplotype combinations were grouped (A to E) based on their frequencies among CD. Binary logistic regression analysis documented a strong association between CD and HLA (OR for intermediate risk haplotypes=178; 95% CI:24-1317; OR for high risk haplotypes=2752; 95% CI:287-26387), but also an HLA-independent correlation between CD and TNFA haplotype combination groups. The CD risk for patients carrying an intermediate risk HLA haplotype could be sub-stratified by TNFA haplotype combinations.TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk.
Project description:Introduction:Methotrexate therapy improves lung function in selected sarcoidosis patients. Variation in TNF gene was associated with response to treatment. Aim: To determine the predictive role of-308 G/A, -857C/T, -863 C/A and -1031 T/C TNF-? polymorphism in the efficacy of MTX for progressive pulmonary sarcoidosis. Material and Methods:Twenty-eight sarcoidosis patients treated with MTX (6-24 months) were genotyped for TNF-? polymorphisms: -1031 T/C, -857C/T, -308 G/A and -863 C/A. Pulmonary function test (PFT) were performed every 6 months to determine treatment response, until the drug withdrawal. Results:No correlation between the initial clinical presentation of sarcoidosis and TNF ? polymorphisms was found, neither for every allele nor for combined genotypes distribution. According to PFT evaluation we have discovered 3 types of response to MTX: early (ER), late (LR) and No-response (NR). TNF-?-308 A allele carriers have got significantly higher chance to be LR, p=0.02, RRI:83%. TNF-?-308 GG genotype transferred the 3-fold higher probability of early vs late response to MTX, p=0.02. Combined genotyping allowed to distinguish LR from ER and NR groups. ER and NR patients are genetically similar (-857CC-308GG). LR are "genetically" different group of patients (-857C/T-308GG or -857CC-308A/G) with 5-fold greater probability to be LR than TNF-?-857CC-308GG patients, p=0,005 sensitivity 85%, specificity: 43%, PPV 58%, NPV 75%. TNF-?-308GG-857CC patients have significantly lower chance to be LR comparing to other response type p=0.03 OR=0,075 95% CI=0.07-0.08. Conclusion:Two types of positive response to MTX therapy (early and late) in chronic respiratory sarcoidosis are associated with polymorphic changes in TNF gene.
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.
Project description:We investigated whether polymorphisms (SNPs) in the promoter region of TNFA, or in the autoinflammatory TNFRSF1A and MEFV genes, concur with HLA-B27 in enhancing the risk of Spondyloarthritis (SpA) and/or in predicting the response to anti-TNF? treatment.373 controls and 137 SpA (82 with Psoriatic Arthritis-PsA and 55 with Ankylosing Spondylitis- AS; 98/137 under TNF? inhibitor therapy) from the Veneto Region (Italy) were studied. TNFA polymorphisms (-1031T>C;-857C>T;-376G>A;-308G>A;-238G>A) and HLA-B27 were assayed by RT-PCR. Direct sequencing of MEFV (exons 2,3,5 and 10) and TNFRSF1A (exons 2,3,4 and 6) genes were performed.HLA-B27 was associated with AS (?2 = 120.1; p = 0.000). Only the TNFA -1031T>C was singly associated with SpA, and the haplotype C/G, resulting from -1031T>C/-308G>A combination, was significantly associated with a reduced risk of SpA (OR: 0.67, CI: 0.46-0.97; p = 0.035). Two SNPs were identified in TNFRSF1A, the R92Q (Minor allele frequency-MAF = 0.034) and c.625+10A>G (MAF = 0.479). None of them was associated with SpA (p>0.05). The TNFRSF1A c.625+10 G allele was associated with late response to anti-TNF? therapy (p = 0.031). Twenty-one SNPs were identified in MEFV gene, 10 with a known potential functional significance. Variant alleles were extremely rare in our population (MAF<0.025) except for R202Q (MAF = 0.27). None was associated with SpA diagnosis (p>0.05).TNFRSF1A and MEFV gene SNPs are not associated with SpA in the North-East of Italy. AS risk appears to depend not only on HLA-B27, but also on the protective TNFA haplotype -1031C/-308G. The TNFRSF1A c.625+10A>G impacts on the response to anti-TNF? therapy.
Project description:BACKGROUND: TNF-α promoter polymorphism has been known to be a potential predictive factor in patients with HBV infection. We therefore tried to investigate whether the TNF-α promoter polymorphism at position -238, -857 and -863 was associated with the outcome of HBV infection in a population from Orissa, southern part of East India. METHODS: A total of 195 patients recruited for the study were classified into 85 controls and 110 HBV infected cases, which included 34 IC, 30 CLD, 32 LC and 14 HCC patients. The polymorphisms at the respective sites were detected by a PCR-RFLP followed by statistical analysis. RESULTS: The frequency of the genotype -238 GG and the allele -238G in the cases (89.0% and 92.7% respectively) was significantly higher than that in the controls (68.2% and 82.2% respectively) (P < 0.001, OR = 3.8 and P = 0.001, OR = 2.73). Whereas the -238 GA genotype was significantly high in the control group (28.2%) when compared to the cases (7.2%) (P < 0.001, OR = 0.2). Similarly, the frequency of -863CC and the allele -863C was significantly higher among the cases (24.5% and 49.5%) compared to controls (1.17% and 34.7%), (P < 0.001, OR = 27.32 and P = 0.003, OR = 1.85), whereas the -863CA genotype was significantly high in the controls (67.0%) when compared to the cases (50.0%) (P = 0.01, OR = 0.49). Haplotype -863C/-857C/-238G in cases was significantly higher than controls (P = 0.002). Multivariate logistic regression analysis indicates that the genotype -863CC bears a negative association with liver disease progression. CONCLUSION: The present study established an association of polymorphisms at site -238 and -863 of the TNF-α promoter with the outcome HBV infection and disease progression.
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:Background:Tumor necrosis factor-alpha (TNF-?) is an important cytokine in acute inflammatory response to infective factors. Based on investigation in different populations, it is thought that this response increases in patients with endometriosis due to the presence of cytokines such as TNF-?. This study aimed to examine the association of four TNF-? polymorphisms, namely -238G/A, -308G/A, -857C/T and -863C/A, with susceptibility to endometriosis in an Iranian population. Materials and Methods:We recruited 150 women with endometriosis and 150 women without endometriosis in this case-control study and collected 4 ml of blood from all subjects. After DNA extraction, the polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results:The allele frequency of TNF-? -863C/A in the case and control groups showed a significant difference [odds ratios (OR)=0.64, 95% confidence interval (CI)=0.41-0.99, P=0.047] but the result is not significant when Adjusting for multiple testing (P=0.188). No significant difference in the allele frequencies of -238G/A (OR=1.07, 95% CI=0.51-2.25, P=0.862), -308G/A (OR=0.79, 95% CI=0.43-1.45, P=0.438) and -857C/T (OR=1.03, 95% CI=0.66- 1.61, P=0.887) was observed. We adjusted all four polymorphism genotypes by age and body mass index (BMI), however, no significant difference was detected. There was an association between the case and control and BMI when adjusting by age (OR=1.082, 95% CI=1.009-1.162, P=0.028). Conclusion:For the first time the association of the four polymorphisms in the promoter region of the TNF-? gene with endometriosis has been conducted in women of Iranian origin. The present research reveals the -863 A allele may play a role in incidence of endometriosis among Iranian women. Development of endometriosis among those people with -863 A allele seems low. According to the results, the current study indicates that there might be a correlation between BMI and progression of endometriosis.
Project description:The association between tumor necrosis factor-alpha (TNF-?-308G/A, -238G/A, -863C/A, -1031T/C, and -857C/T) polymorphism and either chronic (CP) or aggressive (AgP) periodontitis susceptibility was conflicting. This meta-analysis aimed to quantitatively estimate the association.A total of 52 studies involving 5519 patients and 7260 controls were identified through a search of multiple electronic databases. Odds ratios (ORs) and their 95% confidence intervals using allele, homozygous, heterozygous, dominant, and recessive genetic models were computed to assess the strength of the association.The TNF-?-308G/A polymorphism was significantly associated with decreased risks of CP (GG vs AA: OR?=?0.353, P?<?.001; GG+GA vs AA: OR?=?0.480, P?<?.001) and AgP (G vs A: OR?=?0.651, P?<?.001; GG vs AA: OR?=?0.306, P?<?.001; GG+GA vs AA: OR?=?0.384, P?<?.001) in Asians. There were no associations between TNF-?-238G/A, -863C/A, -1031T/C, -857C/T polymorphism and susceptibility to AgP. No associations were also found between CP susceptibility and TNF-?-238G/A, -857C/T polymorphism.These findings supported that TNF-?-308G/A polymorphism might be the protective factors of CP and AgP in Asians, and TNF-?-238G/A, -863C/A, -1031T/C, -857C/T polymorphism is not linked to AgP susceptibility.
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.