TNF-α Gene Promoter Polymorphisms Research Articles

Tumor Necrosis Factor Alpha (TNFα) Gene Promoter Polymorphisms and Haplotypes are Associated with the Febrile Seizure (FS) and TNFα Serum Levels.

Febrile seizure (FS) is a neuroinflammatory disease involving fever-induced seizures affecting children in the early stages of life. TNFα is a pro-inflammatory cytokine reported to be elevated in FS. Specific promoter variants of TNFα could be associated with its elevated cytokine expression and susceptibility to FS. The present study analyzed the association of specific TNFα variants, including TNFα -238 G/A (rs361525), TNFα -308 G/A (rs1800629), and TNFα -376 G/A (rs1800750) promoter polymorphisms, with FS susceptibility, and TNFα serum levels in an Iranian population. Sixty-eight FS patients and 136 controls were enrolled. The SSP-PCR method was utilized to analyze TNFα promoter genotypes. This research also confirmed the genotyping results by sequencing samples of ten patients and normal controls. The GG genotype of -238 SNP was associated with the increased risk of FS [OR = 12.65, 95% CI (2.83-56.60), P-value = 0.0012]. The AA genotype in the-308 region was increased in patients with FS and associated with the disease [OR = 4.62, 95% CI (1.46-14.56), P-value = 0.028]. The increased occurrence of heterozygous AG in the -376 SNP among control groups has been linked to a decreased risk of FS [OR = 0.22, 95% CI (0.11-0.43), P-value = 0.0001]. This study revealed that AGA (-238/ -308/ -376) haplotype with the highest frequency in controls was associated with a decreased risk of FS, while GAA (-238/ -308/ -376) carriers were more susceptible to FS. The current study suggested that TNFα gene promoter variants at rs361525, rs1800629, and rs1800750 could be associated with the susceptibility to FS and altered serum levels of TNFα.

Ассоциация промоторного полиморфизма гена TNF-α с первичной открытоугольной глаукомой

Background: glaucoma is one of the leading causes of blindness worldwide. Diagnosis of glaucoma at an early stage is challenging. Therefore, genetic factors predisposing to the development of primary open-angle glaucoma (POAG) are investigated. One of these predictors is tumor necrosis factor α (TNFα), a multifunctional proinflammatory cytokine involved in glaucoma pathogenesis. Point mutations in the regulatory region of the TNFα gene are hypothesized to be associated with POAG risk. Aim: to analyze the polymorphism of three positions of TNFα gene promoters and their complexes in West Siberian Caucasians with POAG and healthy volunteers. Patients and Methods: the study enrolled 401 individuals, i.e., 99 patients with POAG stage 2 and 302 individuals without POAG (randomized control group). All participants signed an informed consent form. Single nucleotide TNFα gene promoter polymorphism (rs361525, rs1800629, rs1800630) was analyzed. Genotyping was performed by restriction analysis of gene amplification products. Results: the occurrence of minor genotype TNF-308*АА was significantly higher in POAG (odds ratio 11.41, p=0.0011). The occurrence of two other genotypes demonstrated no significant differences between groups. Three complex genotypes were positively associated with POAG (TNF-863*CC:TNF-308*AA, TNF-308*AA:TNF-238*GG и TNF-863*CC:TNF-308*AA:TNF-238*GG). We failed to identify any single nucleotide polymorphism or complexes negatively associated with POAG. Conclusion: minor genotype TNF-308*АА is an essential factor of POAG pathogenesis. Two other polymorphic gene variants were associated with POAG as a part of complex genotypes. These findings demonstrate that potential polymorphic associations should be considered in the case-control analysis. Keywords: primary open-angle glaucoma, polymorphism, TNFα gene, gene promoter, complex genotypes. For citation: Shevchenko A.V., Prokof’ev V.F., Konenkov V.I. et al. Association of TNF-α gene promoter polymorphism with primary open-angle glaucoma. Russian Journal of Clinical Ophthalmology. 2022;22(1):11–15 (in Russ.). DOI: 10.32364/2311-7729-2022-22-1-11-15.

Promoter Polymorphism (-308G/A) of Tumor Necrosis Factor-Alpha (TNF-α) Gene and Asthma Risk: An Updated Meta-Analysis.

Background and Aims: The relationship between the promoter polymorphism (-308G/A) of the tumor necrosis factor-alpha (TNF-α) gene and the susceptibility to asthma has been tested in several studies. However, the results have been inconsistent. Therefore, we performed an updated meta-analysis to evaluate the relationship between this promoter polymorphism of the TNF-α gene and the risk of asthma. Methods: Fifty case-control studies were included in this meta-analysis which provided 17,937 controls and 9961 asthma patients. The pooled p-value, odds ratio (OR), and 95% confidence interval (95% CI) were used to investigate the strength of the association of this polymorphism of the TNF-α gene with the risk of asthma. The meta-analysis was carried out by Comprehensive Meta-Analysis software. Results: The results of our meta-analysis revealed that the TNF-α polymorphism (-308, G/A) was strongly associated with the risk of asthma (p < 0.05 in the allelic, dominant, and recessive models, respectively). In further analyses, based on age group and ethnicity, we observed this association for all subpopulations examined (p < 0.05 in allelic, dominant, and recessive models, respectively). Conclusion: This large-scale meta-analysis supports a strong association between the TNF-α gene promoter polymorphism (-308G/A) and the development to asthma in both children and adults.

DETECTION OF TUMOR NECROSIS FACTOR- (TNF- ) GENE PROMOTERS POLYMORPHISM AMONG LIVER CIRRHOSIS PATIENTS WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IN SURABAYA, INDONESIA

Polymorphisms in TNF-α gene promoter region are known of its role in the production of TNF-α which may influences the pathogenesis of liver disease. SNPs in positions 238 and 308 of TNF-α gene promoters may affect the production of these cytokines. This study was aimed to detect Single Nucleotide Polymorphism (SNP) on -238 and -308 positions in the TNF-α gene promoter among liver cirrhosis patients with HBV infection in Surabaya, Indonesia. This was descriptive exploratory research with cross sectional study design using serum liver cirrhosis patients with HBV infection in Endoscopy Outpatient Clinic Dr. Soetomo General Hospital, Surabaya from April-May 2017. SNPs at -238 and -308 on TNF-α gene promoter (rs361525 and rs1800629 respectively) were detected using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) with primers specific for the TNF-α promoter region and restriction enzymes NcoI and MspI. The genotypes of TNF-α gene promoter were assessed according to the length of the fragments produced in RFLP. Serum TNF-α levels was measured by commercial ELISA. In this study, as much as 149 positive HBsAg patients was found in Endoscopy Outpatient Clinic, Dr. Soetomo General Hospital, Surabaya. From those amount, as much as 30 liver cirrhosis patients with positive HBsAg were obtained. From 2/30 (6.7%) patients showed the GA heterozygote SNP either position -238 or -308. No patient had the AA genotype. Median blood TNF-α level in women (38 ng / L) was higher than in men (33 ng / L). TNF-α levels in patients with GA heterozygote genotype at -238 and -308 in this research was not different than wild-type (GG genotype). Among patients with liver cirrhosis due to chronic HBV infection in Surabaya, Indonesia, Surabaya, we found GA polymorphisms the TNF-α promoter gene at positions -238 and -308 in 6.7% patients, and did not find homozygous AA polymorphisms. Further studies including larger numbers of patients from various ethnic backgrounds in Indonesia are needed to provide robust data on TNF-α gene promoter polymorphisms and their role in the pathogenesis of liver cirrhosis with HBV infection in this country.

Tumor necrosis factor-alpha −308G/A gene polymorphism and novel biomarker profiles in patients with Takayasu arteritis

BackgroundTakayasu arteritis (TA) is an idiopathic chronic inflammatory disease of the aorta and its branches, leading to stenosis, occlusion, and aneurysmal dilatation. Tumor necrosis factor-alpha (TNF-α) is a cytokine with pleomorphic actions and plays a pivotal role in inflammation; the serum level of TNF-α is genetically determined. However, the literature lacks adequate information on the association of TNF-α polymorphisms with TA. Hence, the present study investigates the contribution of TNF-α polymorphism toward the complex etiology of TA. MethodsA cross-sectional study was performed in 87 patients with TA and 90 controls. A promoter region polymorphism of TNF-α, rs1800629 G/A, or −308G/A was genotyped in all the study subjects followed by a case–control association study. Furthermore, to understand the biomarker profile, levels of specific markers such as erythrocyte sedimentation rate, serum high-sensitivity C-reactive protein, interleukin-18, interleukin-6, and TNF-α were measured in all the study subjects. ResultsAll the inflammatory markers were significantly higher in the TA patients than in the controls. The genetic study (available for 57 TA patients and 36 controls) revealed that the TNF-α −308A allele was overrepresented in the TA patients (12% vs 7%). The TNF-α −308A allele correlated with the increased TNF-α levels, but it could not attain significance because of a small sample size. ConclusionThe TNF-α −308G/A polymorphism is associated with TNF-α levels in Indian population, which might have implications for clinical risk stratification and treatment. The different TNF-α gene promoter polymorphism might contribute to the molecular pathogenesis of TA. However, further study of the underlying mechanism is warranted.

Association of tumor necrosis factor-α (TNF-α) gene promoter polymorphisms with aggressive and chronic periodontitis in the eastern Indian population.

Background: Periodontitis is a very common inflammatory oral disease. Tumor necrosis factor-α (TNF-α) is a cytokine that has been involved with the gingival tissue destruction and remodeling occurrence. We investigated the association of single nucleotide polymorphisms (SNPs) in TNF-α gene promoter region with the susceptibility of aggressive and chronic periodontitis in the eastern Indian population.Methods: A total of 397 DNA samples from venous blood were isolated. 40 individuals were aggressive periodontitis patients, 157 were identified chronic periodontitis patients, and the remaining 200 were healthy individuals. Five SNPs of TNF-α at promoter region (rs361525, rs1800629, rs1799724, rs1800630, and rs1799964) were genotyped by PCR-sequencing in periodontitis patients and control subjects.Results: rs1800629 (-308G/A) polymorphism was more frequent in both aggressive and chronic periodontitis patients compared with the control population, though the allele frequency was different only in aggressive periodontitis patients. On the other hand, both the genotypic and allelic variation of rs361525 (-238G/A) polymorphism were found significantly less frequently in aggressive and chronic periodontitis than in controls. The other polymorphisms like rs1799724 (-857C/T) and rs1799964 (-1031T/C) were significantly different between chronic periodontitis patients and control subjects.Conclusion: The findings suggest that the rs1800629 (-308G/A) polymorphism of TNF-α gene is associated with both aggressive and chronic periodontitis while rs1799724 (-857C/T) and rs1799964 (-1031T/C) polymorphisms of TNF-α gene is associated only with the increased susceptibility to chronic periodontitis.

Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression

BackgroundDiabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. MethodsWe screened nine genetic variations in three cytokine genes (TNF-α, IL-6 and IL-β) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). ResultsIndividual SNP analysis showed highest association of IL-1β rs16944-TT genotype (OR = 3.51, 95%CI = 2.36–5.21, P = 0.001) and TNF-α rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64–4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3–14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1–28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-α expression was increased by more than four-folds (n-fold = 4.43 ± 1.11) in DN. TNF-α, IL-6 and IL-1β transcript levels were significantly modulated by promoter region SNPs. ConclusionsThe present study implicates a strong association between cytokine TNF-α, IL-6 and IL-1β gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.

Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy

The crucial role of Tumor Necrosis Factor-α (TNF-α) on renal function in patients with Diabetic Nephropathy (DN) has been well documented. The present study was designed to investigate the association of TNF-α [-308G/A, (rs1800629)] single nucleotide polymorphism (SNP) on the susceptibility to DN subjects and to correlate it with the plasma levels of TNF-α along with circulatory TNF-α receptor super family cytokines (sTNFR-1 and sTNFR-2). A total of 756 subjects, were recruited and divided into groups [Group-I, Control (n=218), Group-II, Normoalbuminuria (n=196), Group-IIIa, Microalbuminuria (n=178), Group-IIIb, Macroalbuminuria (n=164)] and were genotyped by PCR-restriction fragment length polymorphism (RFLP). Circulatory levels of TNF-α and sTNFR-1 & sTNFR-2 were measured using multiplex bead based assay. The ‘A’ allele of TNF-α (-308 G/A) SNP was associated with a significant risk for macroalbuminuria subjects (OR: 2.1; 95% CI: 0.8–3.7; P<0.001). A marked stepwise increase was observed in the levels of circulatory biomarkers such as TNF-α, sTNF-R1 and sTNF-R2 from normo to macroalbuminuria subjects. In DN subjects, the TNF-α level was higher in individuals who had mutant AA, than the wild GG genotype of TNF-α gene. Our results conclude that rs1800629 polymorphism in TNF-α gene is associated with renal complications in T2DM subjects.

Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population.

This study was performed with the aim to investigate the correlations of tumor necrosis factor-alpha (TNF-α) gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis (T-MG) in a northern Chinese Han population. Between June 2005 and June 2015, 305 MG patients (150 males and 155 females, MG group) and 293 healthy volunteers (negative control (NC) group) were enrolled in this study. Among the MG patients, there were 121 patients with thymoma-associated MG (T-MG group) and 184 without T-MG (NT-MG group). Enzyme-linked immunosorbent assay (ELISA) was used for the serum TNF-α level. Polymerase chain reaction-restriction fragment length polymorphism was conducted to determine genotype and allele frequencies of TNF-α gene promoter -1031T/C, -857C/T and -863C/A. The haplotype was analyzed with the SHEsis software. Logistic regression analysis was performed for correlations between TNF-α gene promoter polymorphisms and the risk of T-MG. The T-MG group had higher frequencies of the CT/TT genotype and T allele of -857C/T than the NT-MG and NC groups. The frequencies of the CC genotype and C allele of -1031T/C were higher in the T-MG group than in the NT-MG and NC groups, and higher in male patients in the T-MG group than in male patients in the NC group. TTA and TTC haplotypes exhibited lower frequencies in the T-MG group than in the NT-MG group. The ocular MG patients exhibited lower frequencies of the TT genotype and T allele of -857C/T than the generalized MG patients did. The TNF-α level was elevated in the T-MG group compared with that in the NC and NT-MG groups, indicating that the TC+CC and CT+TT genotypes were increased compared with the TT and CC genotypes in the -1031T/C and -857C/T, respectively. Logistic regression analysis suggested that expressions of anti-acetylcholine receptor antibodies, Osserman's classification, -1031T/C and -857C/T polymorphisms and the TTA haplotype were the independent risk factors for T-MG. These findings reveal that TNF-α -1031T/C and -857C/T polymorphisms and the TTA haplotype may be correlated with the occurrence of T-MG in a Northern Chinese Han population.

TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response

ObjectiveTo investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA). Methods74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at positions −163, −244, −238, −376, and −308. ResultsNo SNPs at position −163 were observed, while we observed only SNPs at positions −244 and −376 in the controls. No differences were observed in the prevalence of SNPs at −238 and −308 between JIA and controls. In JIA patients no significant differences were observed between the −238 and −308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of −308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the −238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the −238/−308 GG genotypes presented the higher reduction of disease activity both after 6 (p < 0.01 vs GA and p < 0.01 vs AA) and 12 months from baseline (p < 0.01 vs GA and p < 0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype −308 AA respect to both GA (p = 0.012) and GG (p = 0.016). ConclusionsJIA patients carrying the TNF-α −308 GA/AA and −238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

TNF‐α gene promoter polymorphisms contribute to periodontitis susceptibility: evidence from 46 studies

Tumour necrosis factor-alpha (TNF-α) plays a critical role in the pathogenesis of periodontal disease. TNF-α gene polymorphisms can influence the TNF-α production. Many studies have focused the association between TNF-α gene promoter polymorphisms and periodontitis risk, but these results are still controversial. A meta-analysis was performed to assess the effect of TNF-α -308G/A (rs1800629), -238G/A (rs361525) and -863C/A (rs1800630) polymorphisms on either chronic (CP) or aggressive periodontitis (AgP) risk. Odds ratios (ORs) along with their 95% confidence intervals (CIs) were calculated to assess the strength of the association. Forty-six studies involving 5186 cases and 6683 controls were retrieved and analyzed. The TNF-α -308G/A AA genotype was associated with increased CP risk in Asians, non-smoking Asians and Caucasians, and this polymorphism was significantly associated with elevated risk of AgP in Asians and Caucasians. Asian individuals carrying AA genotype had a significantly increased risk for -863C/A. No significant association was identified between TNF -238G/A polymorphism and CP. These findings supported that TNF-α -308G/A and -863C/A polymorphisms may contribute to the susceptibility of periodontitis.

A single-nucleotide polymorphism in tumor necrosis factor-α (− 308 G/A) as a biomarker in chronic pancreatitis

ObjectiveChronic pancreatitis is a gradual, long-term inflammation of the pancreas that results in alteration of its normal structure and function. The study aims to investigate the role of −308 (G/A) polymorphism of TNF-α gene in chronic pancreatitis. Material and methodsA total of 200 subjects were included in this case–control study. A total of 100 in patients admitted in the Gastroenterology Unit of Gandhi Hospital and Osmania General Hospital, Hyderabad were included in the present study. An equal number of healthy control subjects were randomly selected for the study. The genotyping of TNF-α gene was carried out by tetra-primer ARMS PCR followed by gel electrophoresis. The TNF-α levels were assayed by enzyme-linked immunosorbent assay. ResultsA significant variation with respect to the genotypic and allelic distribution in the disease group when compared to control subjects [OR=2.001 (1.33–3.005), p<0.0001**] was observed. Subjects homozygous for the A allele had higher TNF-α levels compared to G allele. ConclusionThe present study revealed a significant association of the TNF-α gene promoter polymorphism with chronic pancreatitis. Thus, TNF-α genotype can be considered as one of the biological markers in the etiology of chronic pancreatitis.

TNF-α gene promoter polymorphisms and risk of venous thromboembolism in gastrointestinal cancer patients undergoing chemotherapy

BackgroundTNF-α has been proposed as a predictive factor for venous thromboembolism (VTE). Genetic polymorphisms could regulate TNF-α production. However, the relationship between TNFA gene variants and VTE is not clarified. This study aims to investigate the predictive role of five different TNFA gene promoter SNPs, or their haplotype combination(s), for a first VTE episode in gastrointestinal cancer out-patients treated with chemotherapy. Patients and methodsSerum TNF-α levels and TNFA -863C/A, -857C/T, -376G/A, -308G/A and -238G/A gene promoter polymorphisms were retrospectively evaluated in 314 subjects, including 157 controls and 157 Caucasian patients with histologically diagnosed GI cancers beginning chemotherapy delivery (5-fluorouracil either as monotherapy or in combination with platinum compounds or irinotecan). ResultsHaplotype analysis showed that a five-loci haplotype (CTGGG haplotype) has higher frequency in GI cancer patients who developed VTE (n = 15) during chemotherapy [odds ratio = 2.7, 95% confidence interval (CI) 1.04–7.11, P = 0.04]. GI patients who remained VTE-free did not differ in CTGGG haplotype frequency from controls. No association was observed between serum TNF-α levels and TNFA haplotype, but both were independent predictors of VTE. Approximately 20% of GI cancer patients carrying the CTGGG haplotype developed VTE compared with 4% of the remaining 101 patients (hazard ratio = 5.6, 95% CI 1.8–17.6, P = 0.003). ConclusionThese results suggest that TNFA might represent a candidate gene contributing to VTE pathogenesis in GI cancer patients and suggest that VTE risk during chemotherapy might be genetically identified. Validation studies are needed for translation into clinical practice.

Meta-analysis: the relationship between TNF-alpha polymorphisms and susceptibility to primary biliary cirrhosis.

To investigate the possible influence of TNF-α gene promoter polymorphisms in conferring a predisposition to PBC patients. We performed a meta-analysis of nine articles searched from PubMed up to July 2010 that investigated the association between two TNF-α polymorphisms (-308 and -238) and PBC. The data showed no significant association between TNF-α-308, -238 gene polymorphisms and the susceptibility to PBC in the global group (OR=0.95, 95%CI=0.80-1.13, p=0.55; OR=1.00, 95%CI=0.65-1.55, p=0.99, respectively). Stratified by sub-groups (European, American, Asian), TNF -308 minor allele, but not -238, was found to be a protective factor in the European population (OR= 0.81, 95%CI=0.67-0.99, p=0.04; OR=0.99, 95%CI=0.55-1.77, p=0.97, respectively). Moreover, no significant difference was observed between TNF-α-308 alleles and PBC when stratified by histological stages (stages I-II, OR=0.68, 95%CI=0.32-1.48, p=0.33; stages III-IV, OR=0.69, 95%CI=0.41-1.15, p=0.15). TNF-α promoter polymorphisms might not be associated with PBC risk. However, studies with larger population of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.

TNF-α polymorphisms and coronary artery disease: Association study in the Korean population

Coronary artery disease (CAD) results from atherosclerosis, a chronic inflammatory disease mediated in part by proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), which is expressed by atherosclerotic plaques. In this study, we investigated whether TNF-α gene promoter polymorphisms affect the incidence of CAD in Koreans by genotyping. 404 Control subjects and 197 patients who previously received a coronary artery stent for the G/A, C/T, and C/A polymorphisms at position −238, −857 and −863, respectively. The G/G, G/A and A/A genotypes at position −238 occurred in 85.8%, 14.2% and 0% CAD patients and 91.8%, 7.9% and 0.3% control subjects, respectively. The G/A polymorphisms at position −238 were significantly associated with CAD when assuming a dominant model of inheritance (OR=1.87; 95% CI=1.10–3.20; P=0.02), and A allele carriers had a significantly increased risk of developing CAD relative to the G allele (OR=1.74; 95% CI=1.04–2.92; P=0.03). However, the polymorphisms at positions −857 and −863 were not associated with CAD. Haplotype-based analysis revealed the CAD and control groups differed significantly in the frequencies of haplotype ACC at positions −238, −857 and −863 (OR=1.77; 95% CI=1.05–2.98; P=0.03). This was confirmed by multivariate analysis after adjusting body mass index and the presence of diabetes and hypertension (OR=2.06; 95% CI=1.15–3.68; P=0.015). Thus, the −238A allele of TNF-α is associated with an increased risk of CAD and could be used as predictor for CAD in Koreans. Further studies are needed to elucidate the clinical implications of these findings.

Influence of Polymorphism −308 G/A of the Tnf-α Gene on High Mobility Group Box-1 Protein in Rheumatoid and Spondylo-Arthritis Patients

Single nucleotide polymorphism (SNP) in the human Tumor Necrosis Factor-α(TNF-α) gene promoter, the −308 G/A variant, has been associated with increased TNF-α levels that may amplify the severity of rheumatoid arthritis (RA) and a poor responsiveness to TNF-α blockade therapy. High mobility group box protein (HMGB-1) is a pro-inflammatory cytokine that plays a pivotal role in the pathogenesis of RA and may be an original target of therapy. The aim of this study is to investigate whether the −308 G/A variant of the TNF-α gene is associated with altered expression of HMBG-1. A total of 110 consecutive patients with rheumatoid arthritis and spondylo-arthritis (ankylosing spondylitis, psoriatic arthritis and spondylitis associated with inflammatory bowel disease) referring to the Rheumatology Unit of Messina University Hospital were enrolled. Patients were genotyped for the −308 TNF-α gene promoter polymorphism. Clinical status was also assessed. HMGB-1 and TNF-α mRNA(Real Time PCR) from total blood and plasmatic HMGB-1 (Western Blot analysis) and TNF-α (ELISA) protein were also evaluated. Irrespective of the underlying disease, patients carrying the G/A genotype showed enhanced HMGB-1 and TNF-α mRNA levels and increased circulating concentration of the inflammatory cytokines when compared to patients with G/G genotype. The data suggest that subjects carrying the TNF-α −308G/A genotype have enhanced expression of HMGB-1 protein that may explain, at least in part, the increased severity of the disease.

Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: A meta-analysis

Background/AimsTumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the −308G>A and −238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis. MethodsA meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated. ResultsOur meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case–control studies for the −308G>A polymorphism (OR 0.98; 95% CI 0.83–1.17), and of 480 cases and 302 controls from four studies for the −238G>A polymorphism (OR 0.92; 95% CI 0.58–1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and −308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69–1.24). ConclusionPolymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.

Association of tumor necrosis factor‐α gene promoter polymorphism at sites ‐308 and ‐238 with non‐alcoholic fatty liver disease: A meta‐analysis

Environmental and genetic factors play a role in the pathogenesis and natural history of non-alcoholic fatty liver disease (NAFLD). The objective of this study was to quantitatively evaluate the association between tumor necrosis factor (TNF)-α gene promoter polymorphism at sites -308 and -238 and NAFLD susceptibility. We performed an extensive search of relevant studies and made a meta-analysis, including eight studies with 837 NAFLD cases and 990 controls in the association between TNF-α -308 polymorphism and NAFLD; and seven studies with 771 cases and 787 controls in TNF-α -238 polymorphism. The combined results showed that there was a significant difference in TNF-α-238 genotype distribution between NAFLD and control based on all studies (GA/AA vs GG [odds ratio = 2.06, 95% confidence interval = 1.58-2.69, P < 0.000,01]). However, the combined results based on all studies showed there was no evidence of association of TNF-α-308 genotype distribution between NAFLD cases and controls (GA/AA vs GG [odds ratio = 1.08, 95% confidence interval = 0.82-1.42, P = 0.60]). When stratifying for race, the significant results did not change materially compared with whole populations. This meta-analysis suggested that TNF-α gene promoter polymorphism at position -238 but not -308 might be a risk factor for NAFLD.

Association of TNF-α and Fas gene promoter polymorphism with the risk of Kashin–Beck disease in Northwest Chinese population

The objective of this study is to investigate the relationship between single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor-α (TNF-α) and Fas genes and Kashin-Beck disease (KBD) in Shaanxi province, Northwest in China. Blood samples of 388 residents were collected from 14 KBD villages in Linyou and Yongshou counties, Shaanxi, Northern of China. One hundred eighty-six cases with KBD and 202 cases of health in KBD areas were diagnosed by "Diagnosis Criterion of Kashin-Beck disease in China (WS/T207- 2010)". The TNF-α -308G/A, TNF-α -238G/A, and Fas -670A/G SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in combination with sequence analysis in KBD and healthy control groups. The genotypes and allele frequencies distribution of these SNPs were then analyzed. TNF-α -308A allele frequency in KBD patients were significantly higher than that in healthy controls. Although TNF-α -238 genotypes and allele frequencies were not significantly different between KBD patients and the healthy controls, GA genotype and A allele frequency in KBD patients were higher than those in healthy controls. The TNF-α -308G/A SNPs were associated with the susceptibility of KBD.

Association of tumor necrosis factor-α gene promoter polymorphisms (-308G/A, -238G/A) with recurrent spontaneous abortion: a meta-analysis

Tumor necrosis factor-α (TNF-α) gene promoter polymorphisms (-308G/A, -238G/A) have been associated with increased recurrent spontaneous abortion (RSA) risk, but the results of published articles are controversial. Hence, a meta-analysis was performed to assess the effect of TNF-α -308G/A, -238G/A polymorphisms on RSA risk. Heterogeneity testing and sensitivity analysis were performed using RevMan 5.0 software. Publication bias was assessed by the funnel plot method and modified Egger's linear regression test. In 12 studies for the TNF-α -308G/A polymorphism, the summary odds ratio (OR) with the corresponding 95% confidence interval (95% CI) was 1.04 (95% CI: 0.86, 1.26) under a fixed-effect model in the overall population. In 5 studies for the TNF-α -238G/A polymorphism, the summary OR with the corresponding 95% CI was 1.11 (95% CI: 0.60, 2.03) under a random-effect model in the overall population. We could not identify the sources of heterogeneity for TNF-α -238G/A. In addition, no evidence of publication bias was detected. The results of this meta-analysis indicate that TNF-α -308G/A, -238G/A polymorphisms are not significantly associated with the risk of RSA in the overall population. However, more convincing evidence is required to draw a solid conclusion on the relation between the TNF-α -238G/A polymorphism and the risk of RSA.