Is there a future for TNF promoter polymorphism?

Department of Human Genetics, Leiden University Medical Center, Leiden, The 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
    • "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.
    Human immunology 07/2015; DOI:10.1016/j.humimm.2015.06.016 · 2.14 Impact Factor
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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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    Biotechnology & Biotechnological Equipment 11/2014; DOI:10.1080/13102818.2014.972147 · 0.30 Impact Factor
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    • "TNF-α production shows a wide variation, with high-and low-producer phenotypes present in humans [10], pointing to the influence of genetic variation on the regulation of TNF-α circulating levels. The promoter area of Afaf K. Mousa et al.: TNF-α Genetic Polymorphisms and its Expression in Egyptian Rheumatoid Arthritis Patients the TNF-α gene contains some single nucleotide polymorphisms (SNPs) which control the activity of the promoter and the resulting mRNA and protein levels [11]. Some studies in many parts of the world have addressed the issue of TNF-α gene promoter SNPs and RA outcome. "
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    ABSTRACT: Rheumatoid arthritis (RA) is a complex, multifactorial, inflammatory disease that affects more than 1.5 million adults. The current study aimed to investigate whether there is an association between either-376 G/A or-238 G/A polymorphisms of TNF-α promoter and the risk of RA in Egyptian patients, and investigate whether these polymorphisms are linked to TNF-α expression. DNA from 54 clinically confirmed RA patients and 24 apparently healthy individuals was genotyped by RFLP technique. Some samples were selected for semi-quantitative measurement of TNF-α mRNA expression. For the-376 polymorphism, no polymorphism was recorded in this site neither in RA patients nor in the apparently healthy individuals. This indicated the wide distribution of the wild type GG genotype among Egyptians. For the-238 G/A polymorphism, data indicated that 77.8% of RA patients were of the genotype GG and 22.2% were heterozygous (GA), while 91.7% of the apparently healthy individuals were of the genotype GG and 8.3% were heterozygous (GA). The homozygous genotype AA was not recorded in any RA or healthy subject. There was no statistically significant difference in the genotype distribution between RA patients and the apparently healthy individuals. Also, there was no statistically significant difference in either the G or A allele distribution between the RA group and the group of healthy subjects. Semi-quantitative PCR on some samples revealed a statistically significant increase in the relative expression of TNF-α mRNA in RA patients compared to healthy subjects. Based on these data, we conclude that-238 G/A and-376 G/A polymorphisms can not be considered as risk factors for RA among Egyptians and the increased expression of TNF-α in Egyptian RA patients is not linked to these polymorphisms. Therefore, Egyptian RA patients may have different genetic or environmental factors contributing to the pathogenesis of RA and further studies are necessary to search for other genetic polymorphisms and/or genes that contribute to the increased expression of TNF-α and hence the pathogenesis of RA in Egyptian patients.
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