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University of Western Australia

1. Karimi, Mahdad. Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter.

Degree: PhD, 2007, University of Western Australia

[Truncated abstract] Tumor Necrosis Factor (TNF) is a potent pro-inflammatory cytokine involved in a range of biological functions including the differentiation, proliferation and survival of many cell types. The TNF gene lies in the class III region of the major histocompatibility complex (MHC), approximately 250 Kbp centromeric of the HLA-B locus and 850 Kbp telomeric of HLA-DR. Due to the genomic location and biological relevance of TNF, it is thought that genetic heterogeneity at this locus may be associated with autoimmune and infectious diseases. A G-to-A single nucleotide polymorphism (SNP) at position -308 (relative to the transcriptional start site) in the TNF promoter has been well described. The less common -308A variant has been shown to be linked with the HLA-A1, B8, DR3 haplotype which in turn has been associated to a high TNF producing phenotype. Determining whether the -308 polymorphism contributes to elevated levels of expression has therefore been a priority for many research groups. Some investigators have shown differences in transcription between the -308G and -308A alleles while others could not. These contradicting results have led to conflicting views regarding the functional relevance of the -308 SNP. In this study, statistical analysis of 18 independent transient transfections of -308 biallelic TNF reporter constructs have provided evidence for a functional consequence of the polymorphism. ... In addition, chromatin accessibility of this region was maximal at greater levels of transcription suggesting a role for both chromatin structure and YY1 binding in -308G regulation. Surprisingly, chromatin structure did not seem to play a role in -308A regulation nor was there any significant binding of YY1, suggesting the -308 region does not affect transcriptional control of TNF. Taken as a whole, the G-to-A SNP relieves YY1 binding and demonstrates an allele-specific regulatory mechanism controlling expression. A growing list of promoter polymorphisms exists in the human genome having associations with certain diseases. Determining the functional consequence of these SNPs has proven difficult and utilized mainly in vitro approaches. In this thesis, a unique approach to investigating the functionality of promoter polymoprhisms has been developed, utilizing in vivo techniques which test their effects in a more natural system. It is hoped that the identification of the allele-specific YY1-mediated control of the -308 region of the TNF promoter may provide insight into overexpression as a consequence of the polymorphism and its role in the genetic susceptibility to MHC-associated autoimmune disease.

[Truncated abstract] Tumor Necrosis Factor (TNF) is a potent pro-inflammatory cytokine involved in a range of biological functions including the differentiation, proliferation and survival of many cell types. The TNF gene lies in the class III region of the major histocompatibility complex (MHC), approximately 250 Kbp centromeric of the HLA-B locus and 850 Kbp telomeric of HLA-DR. Due to the genomic…

Subjects/Keywords: Tumor necrosis factor; Genetic polymorphisms; Gene expression; Transcription factors; TNF; SNP functionality; -308 SNP

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APA (6th Edition):

Karimi, M. (2007). Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter. (Doctoral Dissertation). University of Western Australia. Retrieved from http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=9060&local_base=GEN01-INS01

Chicago Manual of Style (16th Edition):

Karimi, Mahdad. “Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter.” 2007. Doctoral Dissertation, University of Western Australia. Accessed December 15, 2019. http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=9060&local_base=GEN01-INS01.

MLA Handbook (7th Edition):

Karimi, Mahdad. “Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter.” 2007. Web. 15 Dec 2019.

Vancouver:

Karimi M. Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter. [Internet] [Doctoral dissertation]. University of Western Australia; 2007. [cited 2019 Dec 15]. Available from: http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=9060&local_base=GEN01-INS01.

Council of Science Editors:

Karimi M. Functional analysis of the -308G/A polymorphism in the tumour necrosis factor promoter. [Doctoral Dissertation]. University of Western Australia; 2007. Available from: http://repository.uwa.edu.au:80/R/?func=dbin-jump-full&object_id=9060&local_base=GEN01-INS01

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