Variant "TNF:c.-308G>A"
Search results: 12 records
Variant information
Gene:
TNF 
Variant:
TNF:c.-308G>A 
Genomic location:
chr6:31543031(hg19) 
HGVS:
SO Term RefSeq
protein_coding NM_000594.3:c.-488G>A
protein_coding NM_000595.3:c.*1561G>A
protein_coding NM_001159740.2:c.*1561G>A
LTA-TNF:n.31543031G>A
Alias:
TNF:c.G308A, TNF:-308G/A(rs1800629), TNF:-308G/A, TNF:(-308)G/A, TNF:rs1800629 
dbSNP ID:
GWAS trait:
no data 
Modifier statisitcs
Record:
12 
Disorder:
Reference:
12 
Effect type:
Expressivity(9) ,Pleiotropy(2) ,Penetrance(1)  
Modifier effect:
Altered severity(3) ,Risk factor(3) ,Altered onset time(2) ,Altered FEV(1)(1) ,Altered FEV1 level(1) ,Altered incidence(1) ,Altered stroke susceptibility(1)  
Details:
  • Target disease:
    Alzheimer's Disease (DOID_10652)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered onset time 
    Evidence:
    P=0.0023 
    Effect:
    At least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising
    Alias in reference:
    TNF:-308G/A
    Reference:
    Title:
    Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease.
    Species studied:
    Human
    Abstract:
    Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-alpha is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60-87) and 240 non-demented age-matched healthy controls for TNF-alpha -308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of -308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the -308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.
  • Target disease:
    Alzheimer's Disease (DOID_10652)
    Effect type:
    Expressivity 
    Modifier effect:
    Risk factor 
    Evidence:
    Assessment of genotype–phenotype associations 
    Effect:
    TNF-alpha G308A polymorphism may be associated with the increased risk of AD in Chinese and decreased risk of AD in northern European populations.
    Alias in reference:
    TNF:c.G308A
    Reference:
    Title:
    TNF-alpha G308A polymorphism and the susceptibility to Alzheimer's disease: an updated meta-analysis.
    Species studied:
    Human
    Abstract:
    Tumor necrosis factor (TNF)-alpha G308A polymorphism has been reported in the association with susceptibility to Alzheimer's disease (AD); however, results have been contradictory. We conducted an updated meta-analysis to evaluate the role of TNF-alpha G308A in the occurrence of AD.
  • Target disease:
    Effect type:
    Penetrance 
    Modifier effect:
    Altered incidence 
    Evidence:
    Heterozygote model: OR: 0.67; 95% CI: 0.49–0.93; q test: 0.581 and recessive model: OR: 0.69; 95% CI: 0.50–0.94; q test: 0.637 
    Effect:
    The G308A polymorphism was only associated with a protective role against CAD
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    Association of G308A and G238A Polymorphisms of the TNF-α Gene with Risk of Coronary Heart Disease: Systematic Review and Meta-analysis.
    Species studied:
    Human
    Abstract:
    It is widely acknowledged that coronary heart disease (CHD) has a genetic influence. One of the most promising candidate genes is tumor necrosis factor-alpha (TNF-α). Although there have been several positive studies associating the TNF-α gene and CHD, the evidence is not entirely consistent. The aim of the study was to evaluate the role of the TNF-α gene in CHD using combined evidence by generating a meta-analysis and a systematic review of all published data.
  • Target disease:
    Cystic fibrosis (DOID_1485)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered FEV(1) 
    Evidence:
    8.1ah comprises linked polymorphisms of major pro-inflammatory cytokines including lta, tnf, hsp and rage. On average, fev1 was significantly lower in 8.1 ah carriers (P<0.04). 
    Effect:
    These findings support the concept that 8.1AH is an important genetic modifier of lung disease in CF.
    Alias in reference:
    TNF:-308G/A
    Reference:
    Title:
    Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients.
    Species studied:
    Human
    Abstract:
    The clinical course of cystic fibrosis (CF) lung disease varies between patients bearing identical CFTR mutations. This suggests that additional genetic modifiers may contribute to the pulmonary phenotype. The highly conserved ancestral haplotype 8.1 (8.1AH), carried by up to one quarter of Caucasians, comprises linked gene polymorphisms on chromosome 6 that play a key role in the inflammatory response: LTA +252A/G; TNF -308G/A, HSP70-2 +1267A/G and RAGE -429T/C. As inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents a lung function modifier in CF.
  • Target disease:
    Cystic fibrosis (DOID_1485)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered severity 
    Evidence:
    OR=5.98, 95% CI:1.06-49.68 
    Effect:
    The -308G>A polymorphism of the TNF-α gene was associated with the CF severity.
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    TNF-alpha polymorphisms as a potential modifier gene in the cystic fibrosis.
    Species studied:
    Human
    Abstract:
    Modifier genes, as the TNF-α gene, can modulate the cystic fibrosis (CF) severity. Thus, -238G>A and -308G>A polymorphisms of TNF-α gene were analyzed as modifiers of CF. In this context, the present study enrolled 49 CF patients (diagnosis performed by sweat test and complete CFTR screening). The -238G>A polymorphism analysis was performed by ARMS-PCR, and -308G>A, by PCR-RFLP. In our data, the -238G>A polymorphism was not associated with clinical variability. The AA genotype for -308G>A polymorphism was a risk factor for early gastrointestinal symptoms (OR=5.98, 95%CI=1.06-49.68) and protection for the first Pseudomonas aeruginosa (OR=0.05, 95%CI=0.0003-0.007). For the first P. aeruginosa, GA genotype was a risk factor (OR=10.2, 95%CI=1.86-84.09); for the same genotype, the diagnosis was made in minor time than the AA genotype (p=0.031). Considering the -308G>A polymorphism alleles, the G allele was a risk factor for early pulmonary symptoms (OR=3.81, 95%CI=1.13-12.97) and P. aeruginosa (OR=66.77, 95%CI=15.18-482.7); however, the same allele showed better transcutaneous oxygen saturation (OR=9.24, 95%CI=1.53-206.1). The A allele was a protective factor for early pulmonary symptoms (OR=12.26, 95%CI=0.08-0.89) and P. aeruginosa (OR=12.15, 95%CI=0002-0007), however, the same allele was a risk factor for worst transcutaneous oxygen saturation (OR=7.01, 95%CI=1.14-157.4). As conclusion, the -308G>A polymorphism of the TNF-α gene was associated with the CF severity.
  • Target disease:
    Cystic fibrosis (DOID_1485)
    Effect type:
    Expressivity 
    Modifier effect:
    Altered severity 
    Evidence:
    P=0.02 
    Effect:
    The genetic factor has been identified which appear to influence disease severity in cystic fibrosis.
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis.
    Species studied:
    Human
    Abstract:
    Disease severity in patients with cystic fibrosis shows marked variability. Attempts to explain this phenotypic heterogeneity on the basis of CFTR genotype have had limited success. A study was undertaken to test the hypothesis that naturally occurring variants of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) and the detoxifying enzyme glutathione S-transferase M1 (GSTM1) could influence disease severity in cystic fibrosis.
  • Target disease:
    Cystic fibrosis (DOID_1485)
    Effect type:
    Pleiotropy 
    Modifier effect:
    Altered FEV1 level 
    Evidence:
    From review article 
    Effect:
    Lower FEV1 predicted associated with the G/A genotype
    Alias in reference:
    TNF:rs1800629
    Reference:
    Title:
    Modifier genetics: cystic fibrosis.
    Species studied:
    Human
    Abstract:
    Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in the Caucasian population, affecting about 30,000 individuals in the United States. The gene responsible for CF, the CF transmembrane conductance regulator (CFTR), was identified 15 years ago. Substantial variation in the many aspects of the CF phenotype among individuals with the same CFTR genotype demonstrates that factors independent of CFTR exert considerable influence on outcome in CF. To date, the majority of published studies investigating the cause of disease variability in CF report associations between candidate genes and some aspect of the CF phenotype. However, a definitive modifier gene for CF remains to be identified. Despite the challenges posed by searches for modifier effects, studies of affected twins and siblings indicate that genetic factors play a substantial role in intestinal manifestations. Identifying the factors contributing to variation in pulmonary disease, the primary cause of mortality, remains a challenge for CF research.
  • Target disease:
    Effect type:
    Expressivity 
    Modifier effect:
    Altered severity 
    Evidence:
    From review article 
    Effect:
    AGTR1,EDN1,TNF mutations is associated with severity of hypertrophy
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    Modifier genes for hypertrophic cardiomyopathy.
    Species studied:
    Human
    Abstract:
    During the past decade, more than 100 mutations in 11 causal gene coding for sarcomeric proteins, the gamma subunit of AMP-activated protein kinase and triplet-repeat syndromes and in mitochondrial DNA, have been identified in patients with hypertrophic cardiomyopathy (HCM). Genotype-phenotype correlation studies show significant variability in the phenotype expression of HCM among affected individuals with identical causal mutations. Overall, causal mutations account for a fraction of the variability of phenotypes and genetic background, referred to as the modifier genes, play a significant role. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The individual modifier genes for HCM remain largely unknown, and a large-scale genome-wide approach and candidate gene analysis are needed. Current studies are limited to simple polymorphism association studies, which explore the association of functional single nucleotide polymorphisms in genes implicated in cardiac growth with the severity of the clinical phenotypes, primarily cardiac hypertrophy. Several potential modifier genes including genes encoding the components of the renin-angiotensin-aldosterone system have emerged. The most commonly implicated is an insertion/deletion polymorphism in the angiotensin-1 converting enzyme 1 gene, which is associated with the risk of sudden cardiac death and the severity of hypertrophy. Therapeutic interventions aimed at targeting the modifier genes have shown salutary effects in animal models of HCM. It has now recognized that modifier genes affect the expression of cardiac phenotype. Identification of the modifier genes will complement the results of studies of causative genes and could enhance genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in patients with HCM.
  • Target disease:
    Effect type:
    Expressivity 
    Modifier effect:
    Altered onset time 
    Evidence:
    P<0.05 
    Effect:
    TNF-α-308A allele is associated with increased MMP-9 activity in SF of patients with early RA and may be a predictor of rapid radiographic progression of disease.
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    Association of tumor necrosis factor-α (G-308A) genetic variant with matrix metalloproteinase-9 activity and joint destruction in early rheumatoid arthritis.
    Species studied:
    Human
    Abstract:
    Matrix metalloproteinases (MMPs) are the key enzymes responsible for the joint destruction. Their activity is regulated by the level of proinflammatory cytokines. The aim of this study was to examine the impact of TNF-α G-308A polymorphism on MMP-9 levels in blood plasma (BP) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and their role in progression of joint destruction. One hundred thirty-four subjects were enrolled in this study. TNF-α G-308A polymorphism was determined using PCR-RFLP method. ELISA assay was used for the detection of MMP-9 activity in BP and SF. Joint damage was estimated by hands and feet radiography. Larsen score and annual changes in LS were used for quantitative evaluation of joint destruction and radiographic progression of disease. MMP-9 activity in BP and SF was significantly higher in RA compared to controls, as well as in SF of patients with erosive compared to nonerosive RA. Faster radiographic progression and increased MMP-9 activity in BP and SF were detected in the group A (GA or AA genotype carriers) compared to the group G (GG genotype carriers). However, statistical significance was revealed only for MMP-9 activity in SF (p < 0.05). MMP-9 activity in BP and SF is significantly higher in RA patients compared to patients with osteoarthritis. The presence of TNF-α-308A allele is associated with increased MMP-9 activity in SF of patients with early RA and may be a predictor of rapid radiographic progression of disease.
  • Target disease:
    Sickle Cell Anemia (DOID_10923)
    Effect type:
    Expressivity 
    Modifier effect:
    Risk factor 
    Evidence:
    OR=3.27; 95% CI: 1.6, 6.9; p=0.006 
    Effect:
    The TNF(-308) G/A promoter polymorphism is a clinically important risk factor for large vessel stroke in children with SCA
    Alias in reference:
    TNF:(-308)G/A
    Reference:
    Title:
    Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia.
    Species studied:
    Human
    Abstract:
    The etiology of stroke in children with sickle cell anemia (SCA) is complex and poorly understood. Growing evidence suggests that genetic factors beyond the sickle cell mutation influence stroke risk in SCA. We previously reported risk associations with polymorphisms in several proinflammatory genes in SCA children with ischemic stroke. The aim of this replication study was to confirm our previous findings of associations between the TNF(-308) G/A, IL4R 503 S/P, and ADRB2 27 Q/E polymorphisms and large vessel stroke risk.
  • Target disease:
    Sickle Cell Anemia (DOID_10923)
    Effect type:
    Pleiotropy 
    Modifier effect:
    Altered stroke susceptibility 
    Evidence:
    Large-vessel stroke: or±se = 0.52±0.17, P=0.048 
    Effect:
    Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 28 genes were independently associated with stroke susceptibility in the LV stroke subgroup. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke.
    Alias in reference:
    TNF:c.-308G>A
    Reference:
    Title:
    Gene interactions and stroke risk in children with sickle cell anemia.
    Species studied:
    Human
    Abstract:
    Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.
  • Target disease:
    Effect type:
    Expressivity 
    Modifier effect:
    Risk factor 
    Evidence:
    Assessment of genotype–phenotype associations 
    Effect:
    The TNFA promoter polymorphism is a leading risk factor for SLE susceptibility in a Bulgarian population.
    Alias in reference:
    TNF:-308G/A(rs1800629)
    Reference:
    Title:
    The Synergistic Effect of TNFA and IL10 Promoter Polymorphisms on Genetic Predisposition to Systemic Lupus Erythematosus.
    Species studied:
    Human
    Abstract:
    We investigated the individual and combined effect of functional TNFA -308G/A and IL10 -1082G/A single nucleotide polymorphisms (SNPs) and their genotypes on the susceptibility to systemic lupus erythematosus (SLE) in a Bulgarian population.