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Title: Functional characterisation of multiple sclerosis-associated single nucleotide polymorphisms in the eomesodermin region
Author: Leach, Oliver
ISNI:       0000 0004 6063 3694
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Multiple sclerosis (MS) is a common inflammatory neurological disease affecting young adults, causing significant disability and increased mortality. Genome wide association studies (GWAS) have uncovered over 100 single nucleotide polymorphisms (SNPs) associated with MS susceptibility, most of which lie outside transcribed DNA and therefore do not have obvious consequences. SNPs in two such non-coding DNA segments upstream of the EOMES gene, encoding Eomesodermin (Eomes) have been consistently associated with MS, as well as with the two other autoimmune diseases rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Eomes has been shown to be important for embryonic and neural development, as well as in the immune system, the latter of which was the focus of this investigation. The association of genetic polymorphisms in the EOMES region with MS was interrogated using computational methods. Imputation analysis enabled detection of new variants, which aligned with regions of epigenetic significance and possible regions of DNA-interaction, implying an effect on regulation of gene expression. Subsequently, Eomes expression was characterised in peripheral blood cell populations, with the highest expression detected in natural killer cells and effector/memory T cell subsets, including MAIT cells, an innate-like lymphocyte population. To investigate potential genotype dependent changes in Eomes expression and the effect on downstream pathways, studies were performed using samples from healthy donors prospectively genotyped for the two MS associated loci. Despite observing significant differences in expression between genotype groups in a pilot study, findings in a larger cohort did not reach the threshold for significance. Finally, the presence of MAIT cells was investigated in the context of MS and these cells were detected in MS lesions. Collectively, in this D.Phil project I have illustrated potential ways in which the functional relevance of disease-associated SNPs in non-coding regions can be studied. This has been thoroughly investigated through computational studies, analysis of gene expression in peripheral blood cells, and in genotype-dependent studies of both expression and downstream function.
Supervisor: Fugger, Lars Sponsor: MS Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available