Is there a future for TNF promoter polymorphism?

Leiden University, Leyden, South Holland, Netherlands
Genes and Immunity (Impact Factor: 2.91). 09/2004; 5(5):315-29. DOI: 10.1038/sj.gene.6364055
Source: PubMed


The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied -308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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Available from: Cor L Verweij, Mar 10, 2014
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    • "Researchers have suggested that inflammation had a predominant role in the development and rupture of atherosclerotic lesions, resulting in cardiovascular disease events (Packard and Libby 2008). The tumor necrosis factor (TNF)-a, one of the most typical pro-inflammatory cytokines, plays a vital role in inflammation and cell signaling (Bayley et al. 2004). Many studies have investigated the association between TNF-a polymorphisms and ischemic stroke susceptibility. "
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    ABSTRACT: A number of studies have investigated the association between tumor necrosis factor (TNF)-α gene polymorphisms and ischemic stroke susceptibility. However, results of different individual studies are often inconsistent. To provide a more robust evaluation of the association between polymorphisms of the TNF-α gene and ischemic stroke risk, we performed a systematic review with multivariate meta-analyses. PubMed, Embase, CNKI, and WanFang databases were searched up to December 20, 2014. Two reviewers independently extracted information and assessed quality of included studies after all the eligible studies were identified. Afterward, multivariate meta-analyses were performed using Stata 13. The estimation of polymorphisms and disease risk was presented by odds ratios (ORs) and corresponding 95 % confidence intervals (CIs). Forty-nine eligible case-control studies from 25 articles that explored the association between 10 TNF-α polymorphisms and ischemic stroke were indentified from aforementioned databases. The results of multivariate meta-analysis showed a significant association between -238G/A polymorphism (4760 patients and 4389 controls) and ischemic stroke risk in heterozygotes compared with wild genotype (AG vs. GG: OR 1.44, 95 % CI 1.11-1.87; AA vs. GG: OR 1.98, 95 % CI 0.73-5.40). No significant association of -308G/A, -857C/T, and -1031T/C polymorphisms was observed. The results of stratification analyses of -238G/A polymorphism showed that the AG genotype only increased the risk of ischemic stroke in Asians compared to GG genotype. No additional significant association was observed in this study. In conclusion, the present systematic review and meta-analysis support a prominent role of the TNF-α -238G/A polymorphism in the risk of ischemic stroke in Asian adults only, but do not support the role of -308G/A, -857C/T, -1031T/C, -244G/A, -367G/A, -646G/A, -806C/T, -863C/A, and +448G/A in the risk of ischemic stroke. The current evidence warrants further studies with high quality and large sample size to confirm.
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    • "sidering that cytokines play a pivotal role in the host - parasite interaction , and since the ability to produce cytokines in different individuals may be attributable to polymorphisms at cytokine regulatory gene regions or coding gene region [ Barbulescu et al . , 1998 ; Puren et al . , 1998 ; Pravica et al . , 2000 ; Giedraitis et al . , 2001 ; Bayley et al . , 2004 ] , cytokine gene polymorphisms may influence the natural his - tory , and clinical outcome of infections . This could particularly be the case for HBV infection , in which less than 20% of infected individuals may be chronic carriers of the virus and present chronic liver compli - cations [ Bataller et al . , 2003 ; Xu et al . , 2005 ;"
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    ABSTRACT: HLA-E is a non-classical Human Leucocyte Antigen class I gene with immunomodulatory properties. Whereas HLA-E expression usually occurs at low levels, it is widely distributed amongst human tissues, has the ability to bind self and non-self antigens and to interact with NK cells and T lymphocytes, being important for immunosurveillance and also for fighting against infections. HLA-E is usually the most conserved locus among all class I genes. However, most of the previous studies evaluating HLA-E variability sequenced only a few exons or genotyped known polymorphisms. Here we report a strategy to evaluate HLA-E variability by next-generation sequencing (NGS) that might be used to other HLA loci and present the HLA-E haplotype diversity considering the segment encoding the entire HLA-E mRNA (including 5'UTR, introns and the 3'UTR) in two African population samples, Susu from Guinea-Conakry and Lobi from Burkina Faso. Our results indicate that (a) the HLA-E gene is indeed conserved, encoding mainly two different protein molecules; (b) Africans do present several unknown HLA-E alleles presenting synonymous mutations; (c) the HLA-E 3'UTR is quite polymorphic and (d) haplotypes in the HLA-E 3'UTR are in close association with HLA-E coding alleles. NGS has proved to be an important tool on data generation for future studies evaluating variability in non-classical MHC genes. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Human immunology
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    • "Interindividual variations in the TNF production in healthy controls have been observed with high and low producer phenotypes, indicating a substantial genetic contribution to regulation of the TNF synthesis.[3] [4] These findings suggest that polymorphism in the TNF-a regulatory region might influence its production. A number of single nucleotide polymorphisms (SNPs) within the promoter of the TNF-a gene has been identified. "
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    ABSTRACT: In this study, we analyzed the putative association between the -308G/A polymorphism in the promoter region of the tumor necrosis factor (TNF) alpha gene (rs1800629) and chronic inflammatory arthritis in the Bulgarian population. A case-control study was carried out on 58 patients with ankylosing spondylitis (AS), 108 rheumatoid arthritis (RA) patients and 177 healthy subjects. -308G/A TNF-alpha genotypes of patients and controls were determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). No significant association between the rs1800629 polymorphism and RA risk in the study cohort was observed. However, there were significant differences in the genotype and allele frequencies of the -308G/A TNF-alpha polymorphism between AS patients and the healthy subjects. In logistic regression analysis, the presence of the TNF-alpha -308A allele in the genotype (AA + AG vs. GG) was associated with a 3.298times lower risk of developing AS. In addition, in AS, there were associations for age at disease onset (<29years; odds ratio (OR) = 0.222), disease severity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score > 4; OR = 0.152) and response to anti-TNF treatment (OR = 2.25) under a dominant model (AA + AG vs. GG). In conclusion, our results suggested that the promoter polymorphism -308G/A in the TNF-alpha gene had no significant effect on RA development, but could play a role in AS development and in determining the age of disease onset, disease severity and therapeutic outcome of AS in the Bulgarian patients who participated in our study.
    Full-text · Article · Nov 2014 · Biotechnology & Biotechnological Equipment
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