Wilson, A.G., Symons, J.A., McDowell, T.L., McDevitt, H.O. & Duff, G.W. Effects of a polymorphism in the human tumor necrosis factor promoter on transcriptional activation. Proc. Natl Acad. Sci. USA 94, 3195−3199

Section of Molecular Medicine, University of Sheffield, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/1997; 94(7):3195-9. DOI: 10.1073/pnas.94.7.3195
Source: PubMed


Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.

Download full-text


Available from: Anthony G Wilson
  • Source
    • "For example, an over-stimulated immune system in a sepsis patient could be related to genetic polymorphisms affecting protein function and gene expression, resulting in excessive proinflammatory responses (Arcaroli et al. 2005). Accordingly, single nucleotide polymorphisms (SNPs) within the tumour necrosis factor (TNF)-α gene promoter, such as -308 (A/G) (also known as allele TNF2), have been associated with increased promoter activity (Wilson et al. 1997) and increased TNF-α plasma levels in response to lipopolysaccharides (Louis et al. 1998). These biological changes increase the severity of sepsis , including mortality (Mira et al. 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite major improvements in its treatment and diagnosis, sepsis is still a leading cause of death and admittance to the intensive care unit (ICU). Failure to identify patients at high risk of developing septic shock contributes to an increase in the sepsis burden and rapid molecular tests are currently the most promising avenue to aid in patient risk determination and therapeutic anticipation. The primary goal of this study was to evaluate the genetic susceptibility that affects sepsis outcome in 72 sepsis patients admitted to the ICU. Seven polymorphisms were genotyped in key inflammatory response genes in sepsis, including tumour necrosis factor-α, interlelukin (IL)-1β, IL-10, IL-8, Toll-like receptor 4, CXCR1 and CXCR2. The primary finding showed that patients who were homozygous for the major A allele in IL-10 rs1800896 had almost five times higher chance to develop septic shock compared to heterozygotes. Similarly, selected clinical features and CXCR2 rs1126579 single nucleotide polymorphisms modulated septic shock susceptibility without affecting survival. These data support the hypothesis that molecular testing has clinical usefulness to improve sepsis prognostic models. Therefore, enrichment of the ICU portfolio by including these biomarkers will aid in the early identification of sepsis patients who may develop septic shock.
    Full-text · Article · Jun 2015 · Memórias do Instituto Oswaldo Cruz
  • Source
    • "However, it is plausible to consider TNF as a candidate gene because of its involvement in immunemediated beta cell apoptosis and beta cell destruction (Eizirik and Mandrup-Poulsen, 2001). Besides, the -308A risk allele was shown to be associated with higher promoter activity (Kroeger et al., 1997; Wilson et al., 1997) and higher TNF expression than the G allele (Das et al., 2006; Louis et al., 1998) justifying the attempts to unmask a possible minor independent effect of this TNF variant on T1D risk by epidemiologic studies. Another aspect that deserves attention is the ethnic admixture of the Brazilian population that could be a source of false-positive associations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · May 2015 · Gene
  • Source
    • "The presence of regulatory elements are described in the TNF promoter region that may affect the binding site for transcriptional factor [8] [9]. A single nucleotide polymorphism (SNP) À308 G/A seems to influence the transcriptional activity [10] [11]. Other SNPs À1031 T/C, À863 A/C and À857 C/T in the promoter region of the TNF have also been related to differential transcription. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphisms present in the TNF promoter region has shown to influence the gene transcription. Leprosy displays different clinical manifestations according to the immune responses of the individual infected with Mycobacterium leprae. In this study, we evaluated the single nucleotide polymorphisms (SNPs) -238 G/A (rs361525), -308 G/A (rs1800629), -857 C/T (rs1799724), -863 A/C (rs1800630) and -1031 T/C (rs1799964) in the promoter region of the TNF to see whether these SNPs influence host-susceptibility to leprosy and the different clinical manifestation. Nucleotide sequencing was performed with DNA samples from 108 leprosy patients and 253 control subjects. An association between -1031 C/C genotype and protection from leprosy was observed when leprosy patients were compared to controls (OR 0.11; 95% IC = 0.01-0.82; p = 0.012). The -857 C/T genotype may be associated with susceptibility to leprosy (OR = 1.81; 95% IC = 1.09-3.00; p = 0.028). Similar genotype and allele frequencies for the SNPs -308 G/A and -238 G/A were observed between leprosy patients and control subjects. Altogether, TNF polymorphisms in the promoter region may be predictive of leprosy outcome. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Human Immunology
Show more